Physiol Rev 88: 421– 449, 2008; doi:10.1152/physrev.00041.2005.
Ca2⫹-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models BRITT MELLSTRO¨M, MAGALI SAVIGNAC, ROSA GOMEZ-VILLAFUERTES, AND JOSE R. NARANJO Centro Nacional de Biotecnologı´a, Consejo Superior Investigaciones Científicas, Madrid, Spain
I. Introduction: The Encoded Calcium Signal II. The Calcium Toolkit for Posttranslational Modifications A. Ca2⫹/kinase-regulated transcription pathways B. Ca2⫹/phosphatase-regulated transcription pathways III. Calcium-Dependent Transcriptional Networks A. The CREB/CBP/TORC pathway B. The MEF-2 crossroad of Ca2⫹ regulation C. The NFAT family of transcription factors D. The DREAM/KChIP family of Ca2⫹-sensitive transcriptional repressors E. The NF-B /I-B couple F. Novel mechanisms associated with Ca2⫹-dependent gene expression IV. Calcium-Dependent Protein-Protein Interactions That Modulate Gene Expression A. Ca2⫹ sensors in the nucleus B. Ca2⫹-dependent changes in chromatin structure V. Exemplifying the Complexity of Calcium-Dependent Gene Expression: The Brain-Derived Neurotrophic Factor Compendium VI. Summary and Future Directions
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Mellstro¨m B, Savignac M, Gomez-Villafuertes R, Naranjo JR. Ca2⫹-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models. Physiol Rev 88: 421– 449, 2008; doi:10.1152/physrev.00041.2005.—Calcium is the most universal signal used by living organisms to convey information to many different cellular processes. In this review we present well-known and recently identified proteins that sense and decode the calcium signal and are key elements in the nucleus to regulate the activity of various transcriptional networks. When possible, the review also presents in vivo models in which the genes encoding these calcium sensors-transducers have been modified, to emphasize the critical role of these Ca2⫹-operated mechanisms in many physiological functions.
I. INTRODUCTION: THE ENCODED CALCIUM SIGNAL For the last 25 years, great effort has been devoted to understanding and characterizing the molecular mechanisms used by cells to transform a cytosolic Ca2⫹ signal into specific, finely controlled changes in gene expression. Several earlier reviews have addressed the variety of regulatory mechanisms that participate in Ca2⫹-dependent gene expression in neurons (76, 208, 321) and other cells (27, 45, 179). Recent discoveries have added new elements to the “nuclear Ca2⫹ toolkit” and, just as important, new interactions have been reported between players that use Ca2⫹ to tune the function of different transcriptional networks. Furthermore, the spectacular rise of recently developed genetically modified animal models illustrates the universal, though selective, and crucial role www.prv.org
of the calcium signal in the living animal. Advances in the understanding of the role of the calcium signal in regulating gene expression patterns in other organisms, mainly worms, yeast, and plants, have been recently reviewed (19, 68, 333) and are not discussed here. Since the central protagonist in this review is the calcium signal, this introduction will comment on three major characteristics of the calcium signal that determine its final physiological role in the control of transcriptional networks: the specific temporal dynamics of the signal, the subcellular microdomains in which the signal is generated, and the nature of the calcium signal inside the nucleus. In most cells, excitable and nonexcitable, stimulation of cell-surface receptors generates oscillations in intracellular free calcium concentration ([Ca2⫹]i) of variable amplitude and frequency. The oscillatory nature of the cal-
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cium signal was from the beginning understood as a code to explain the different biological activities that it triggered in different cell systems. In a pioneering work, Lewis and colleagues (85) demonstrated that the oscillatory nature of the Ca2⫹ signal was in itself sufficient to enhance the nuclear detection of low-amplitude stimuli, and to reduce the effective Ca2⫹ threshold for activating transcription factors, while for high level of stimulation oscillations did not further increase the response (85). In trying to decipher the encoded information, it was soon obvious that frequency rather than amplitude was the important property of the oscillation for selective activation of one but not other transcriptional networks. Thus the Lewis and the Tsien groups showed in parallel that rapid oscillations stimulated nuclear factor of activated T cells (NFAT) and NF-B-dependent transcription, whereas infrequent oscillations activated only NF-B (85, 181). This effect of oscillation frequency has a physiological correlate in the differential inducibility at rapid and slow oscillations of interleukin (IL)-2 and IL-8, respectively (85), and it was clearly associated with the specific dynamics of posttranslational modifications and nuclear accumulation of these two nuclear effectors, fast and very transient for NFAT and much slower for NF-B (reviewed in 129a). It was long hypothesized that the site of Ca2⫹ entry determined the biological outcome of Ca2⫹ signaling (84, 121). In neurons, calcium flux through N-methyl-D-aspartate (NMDA) receptors or L-type calcium channels is a potent inducer of CREB phosphorylation and brain-derived neurotrophic factor (BDNF) expression. Ca2⫹ entry following glutamate bath application only slightly activates CREB and does not trigger BDNF expression (120, 279, 300). The apparent controversy was solved by Bading and co-workers (122), who showed conclusively that Ca2⫹ entry through extrasynaptic NMDA receptors opposes the increase in CREB phosphorylation and the induction of BDNF expression triggered by Ca2⫹ input through synaptic NMDA channels. Thus expression of BDNF in neurons is regulated by at least two different Ca2⫹ pools, each one associated with specific signaling cascades that lead to opposite biological effects. The mechanism(s) by which extrasynaptic Ca2⫹ shuts off CREB activation is not fully understood, but the action of a glutamate-regulated protein phosphatase 1 (PP1) able to specifically dephosphorylate Ser133CREB was shown in hippocampal neurons (268). This finding is consistent with previous reports (29, 119) and with the proposed role of PP1 in synaptic plasticity (7). How PP1 is specifically activated by extrasynaptic NMDA receptor stimulation and the cellular compartment where it dephosphorylates CREB are questions that remain to be elucidated. In a recent follow-up report, Hardingham and coworkers (236) added further complexity to the calcium signal by showing that within the synaptic site of calcium Physiol Rev • VOL
entry, at least two completely different molecular pathways can be discriminated, conferring acute or long-lasting neuroprotection. Acute survival induced by Ca2⫹ entry through synaptic NMDA channels is thus not mediated by CREB-dependent transcriptional activity, but is exclusively related to the activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway. Conversely, in the same study, the authors demonstrate that long-lasting activity-dependent neuroprotection requires CREB family activation and the elevation in nuclear Ca2⫹ or in nuclear Ca2⫹/ calmodulin signaling. In nonexcitable cells, the first Ca2⫹ entry pathway identified was termed store-operated Ca2⫹ entry (SOCE), since it is stimulated in response to depletion of Ca2⫹ from intracellular Ca2⫹ stores in the endoplasmic reticulum (ER). SOCE is mediated via the activation of specific plasma membrane channels, termed store-operated calcium (SOC) channels, which are ubiquitously expressed in all cell types. However, and somewhat uniquely, the biophysical characteristics of the channel are different in various cell types. The first SOC channel to be identified, the calcium-release-activated calcium (CRAC) channel, mediates a highly Ca2⫹-selective calcium current detected in T lymphocytes (9, 230). The molecular entity and the mechanisms that operate the activation of CRAC channels have remained elusive over the years that followed their functional identification (101, 180). Until recently, members of the mammalian TRP family of channels (named after the homologous Drosophila transient receptor potential channel) were considered to be good candidates for forming the CRAC channel (reviewed in Refs. 179, 237). However, TRP channels do not recapitulate the expected biophysical properties of CRAC currents in transfection experiments (247). Concerning the mechanisms for the activation of these currents, several theories were proposed including a direct conformational coupling with inositol trisphosphate (IP3) receptors (146, 159, 161, 195) or the involvement of a diffusive calcium influx factor (CIF) (252, 291). Recently, several proteins that are essential for CRAC channel activity in Drosophila and in mammals have been identified, including the ER Ca2⫹ sensor Stim1 (186, 260) and the transmembrane protein Orai1/CRACM1, which is a pore subunit of the CRAC channel and forms the Ca2⫹selectivity filter of the channel (93, 249, 315, 334, 340). Transient overexpression of either Stim1 or Orai1 alone results in little or no increase in store-operated Ca2⫹ entry, while cotransfection of both proteins results in an increased store-operated Ca2⫹-selective current (241). In basal conditions, the Stim1 protein is located in the lumen of the ER, where it senses Ca2⫹ levels. After store depletion, Stim1 relocalizes into preexisting and newly formed regions of junctional ER lying within 10 –25 nm of the plasma membrane, while Orai1 accumulates at sites in the plasma membrane (PM) directly opposite to Stim1 (186,
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260, 341). There, Stim1 interacts with Orai1 (193, 210, 327). Taken together, these data suggest a model in which the elementary unit of CRAC is represented by ER-PM junctions (192). A similar coupling between the sarcoplasmic reticulum and the plasma membrane was previously described in skeletal and cardiac muscle directing excitation/contraction (299). While in the skeletal muscle there is a direct coordinated bidirectional interaction between plasma membrane L-type Ca2⫹ channels (LTCC) and the ryanodine receptor (RyR) in sarcoplasmic reticulum (221), in cardiac muscle calmodulin and Ca2⫹- and calmodulin-dependent protein kinase (CaMK) are required to functionally couple LTCC and RyR during cardiac excitation-contraction coupling (328). The mechanism that regulates CRAC channels has been further advanced by the recent identification of Golli, a negative regulator of the CRAC activation pathway (92). Golli-deficient T cells show enhanced calcium entry after TCR stimulation, while golli⫺/⫺ oligodendrocytes show altered Ca2⫹ transients that are associated with hypomyelinization in the visual cortex and optic nerve (148). Myristoylation-dependent membrane association of Golli is essential for its inhibitory action after calcium influx in T cells (92). Following the discovery of the Stim1 and Orai1 proteins, the potential role of TRP channels in calcium fluxes has been reevaluated, and an emerging role for TRP channels has been disclosed. Thus it has been shown that TRPC1 interacts with Stim1 in a store depletion-dependent manner and that Stim1 is required for the coupling between TRPC1 and type II IP3 receptor (IP3R) in platelets (188). Furthermore, it has also been shown that the structural features of Stim1 that are essential for Stim1dependent activation of CRAC channels are identical to those involved in the binding and activation of TRPC1 in Jurkat T cells (137). Recent evidence showing that the formation of a TRPC1-Stim1-Orai1 ternary complex is essential for the generation of ISOC currents in salivary gland cells suggests a common molecular basis for CRAC in T lymphocytes and SOC in other cells (9, 230). An additional important point, specific to exocrine cells, is the polarized/asymmetric nature of Ca2⫹ handling. Exocrine acinar cells are polarized, and it was therefore of interest to investigate whether Ca2⫹ extrusion has a uniform rate across both faces of the cell or whether there is preferential extrusion in one direction. It has been shown that in acinar cells the basal part is designed for Ca2⫹ uptake from the extracellular fluid into the ER, while the apical part is specialized for Ca2⫹ release from the ER to stimulate the formation of primary fluid and enzyme secretion into the acinar lumen (243). It is therefore favorable for the cells to restrict Ca2⫹ elevations to the apical/granular region. The signal is initiated at the apical pole (303) due to preferential localization of Ca2⫹ release channels in this part of the cell (176, Physiol Rev • VOL
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223). The major mechanism by which the signal is restricted to the apical part of the cell is sequestration of Ca2⫹ by active mitochondria that localize in a “belt” around the granular region (155, 288, 307). These mitochondria accumulate Ca2⫹ during agonist-evoked Ca2⫹ elevations (238). Control of the activity of specific transcriptional networks by Ca2⫹ is regulated by cytosolic and/or nuclear mechanisms that decode the calcium signal specificities in terms of frequency and spatial properties. The regulation of Ca2⫹-dependent transcriptional networks does naturally demand the intervention of nuclear Ca2⫹, but existence of mechanisms that control free calcium concentration within this organelle independently of the cytoplasm remains to this day an unresolved question. A frequently proposed view is that calcium diffuses freely from the cytosol into the nucleus, and back, through nuclear pores (187). However, this view is challenged by a number of observations that support the alternative concept of independent nuclear Ca2⫹ homeostasis (81, 191 for a comprehensive review, but also a number of other specific contributions 197, 240; see Ref. 269). According to the alternative concept, the nuclear pores could be somehow gated and restrict the transient of Ca2⫹ under given physiological situations. About this, we could quote a number of observations, in diverse cell types, that have shown attenuation of cytosolic Ca2⫹ transients at the nuclear envelop, and the demonstration of singlechannel currents in patch-clamped nuclear envelop containing dozens of nuclear pores. The idea of an independently regulated nuclear calcium compartment is conceptually important, as it would imply the existence of similarly independent regulatory mechanisms for the release of this calcium. More importantly, it would also allow us to consider calcium microdomains within the nucleus that would confer additional specificity to calcium effects on chromatin structure and gene expression. In a recent study that extends previous work by other laboratories (97, 103, 118), Nathanson’s group (88) identified a nucleoplasmic reticulum that is continuous with the ER and the nuclear envelope. Like the ER, the nucleoplasmic reticulum expresses IP3Rs that mediate small calcium signals in localized subnuclear microdomains. This calcium signal then triggers the translocation of nuclear protein kinase C (PKC)-␥ to the nuclear envelope in the vicinity of this domain (88). Interestingly, the mechanism can be preferentially triggered by growth factors such as hepatocyte growth factor and involves nuclear translocation of the growth factor receptor, induction of nuclear calcium signals, and the translocation of PKC-␥ to the nuclear envelope without cytosolic PKC redistribution (88). It is presently not known whether increases in nuclear calcium control transcriptional networks through general mechanisms (see below) or if the specific localization of the signal in subnuclear compartments requires
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different mechanisms, such as localized changes at dinucleotide repeats in the DNA structure (83). II. THE CALCIUM TOOLKIT FOR POSTTRANSLATIONAL MODIFICATIONS The first known and best described set of mechanisms by which changes in the intracellular concentration of free calcium can affect gene expression is the activation of several kinases and phosphatases. Both in the cytosol and the nucleus, they introduce posttranslational modifications on appropriate molecules in the transcriptional machinery, resulting in modified expression of specific single genes or in readjustments of the activity of entire transcriptional networks. A. Ca2ⴙ/Kinase-Regulated Transcription Pathways Several kinases are important mediators of calciumdependent gene expression since, in one way or another, their activity is regulated by changes in calcium levels and their substrates are molecules that regulate gene expression. Among the kinases, our focus will be on two major groups, the CaMKs and the “conventional” PKC isoenzymes. A summary of the different Ca2⫹-dependent kinases, their regulation, and specificities is portrayed in this section (Fig. 1). For a more detailed description, see monographic reviews (62, 139, 212, 239). 1. CaMKs The CaMKs (CaMKI, CaMKII, and CaMKIV) are serine/ threonine protein kinases with an NH2-terminal catalytic
domain and a COOH-terminal regulatory domain. The regulatory domain includes the Ca2⫹/calmodulin (CaM) binding domain, which overlaps with an autoinhibitory domain such that autoinhibition is relieved upon Ca2⫹/ CaM binding. In addition, CaMKII has an association domain that permits CaMKII to form multimeric structures, whereas CaMKI and CaMKIV are monomeric enzymes. These kinases are all regulated by phosphorylation, although through different mechanisms. Whereas CaMKI and CaMKIV are phosphorylated by two Ca2⫹/CaM-dependent protein kinase kinases (CaMKK␣ and -), CaMKII binds Ca2⫹/CaM and autophosphorylates at Thr-286. After phosphorylation, phosphoCaMKII shows a 1,000-fold increased affinity for CaM and becomes partially Ca2⫹/CaM independent (reviewed in Ref. 134). In addition, CaMKII activity can also be regulated by proteins that have domains homologous to the CaMKII autoinhibitory domain (114), i.e., the NMDA NR2B subunit (23) or the Drosophila ether-a-go-go (Eag) potassium channel (294). In most cases, these interactions require prior autophosphorylation at Thr-286 to occur, and once in place, the enzymatic activity becomes also Ca2⫹/CaM independent. The fact that kinase activity is preserved for some time after the initial stimulus has ended led to proposals that CaMKII might serve as a memory molecule at synapses and may underlie long-term changes in synaptic activity (reviewed in Ref. 113). The enzyme activity may terminate through the action of specific phosphatases and/or through other autophosphorylation events as is the case of CaMKII, in which autophosphorylation at Thr residues 305 and 306 blocks binding to CaM and inhibits activity of the kinase. Four genes encode CaMKII isoenzymes. Of them, ␣ and 
2⫹ FIG. 1. Molecular mechanisms of Ca -dependent transcription: activity-dependent kinases. Representation of the main transcriptional networks regulated by Ca2⫹/calmodulin (CaM)-dependent protein kinases (CaMKs) and “conventional” Ca2⫹/diacylglycerol (DAG)-dependent protein kinase C isoenzymes (PKC). For details about how these kinases regulate Ca2⫹-dependent transcription, see section IIA in the text.
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are expressed preferentially in neuronal tissue, while ␥ and ␦ are expressed in somatic cells (140). Another important distinction between CaMKs is their subcellular distribution. While at least one CaMKII isoform is predominantly a nuclear enzyme and CaMKIV is largely nuclear, CaMKI is exclusively cytosolic. Among other substrates, CaMKs have been associated with activity-dependent direct phosphorylation of several transcription factors including CREB, CBP, and Ets-1, and to the nuclear translocation of NF-B. In addition, a recent report associates CaMK’s activity with the activity-dependent redistribution of SMRT, a corepressor protein related to transcriptional control through hormone receptors. Thus nuclear export of SMRT follows the nuclear extrusion of class II histone deacetylases (HDAC) and the process is blocked by the CaMKKK inhibitors N-62 and Sto-609 (205). Whether this is a direct mechanism remains to be clarified. It is conceptually important, however, since it could explain the Ca2⫹-dependent potentiation of hormonal effects without direct intervention at the level of nuclear hormone receptors. With such a pleiotropic role in the regulation of gene expression, it could be expected that genetic manipulation of CaMKs results in profound phenotypic changes. In the case of CaMKII␣, which is highly expressed in the forebrain, genetic ablation results in deficient hippocampal long-term potentiation (LTP) (280), abnormal fear response and aggressive behavior (52), increased ischemia-induced neuronal damage (319), and deficient plasticity in the primary visual cortex (109). Outside the brain, expression of a calcium-independent CaMKII␥ mutant in T cells results in increased percentage of peripheral T cells with an antigen-dependent memory phenotype through a mechanism that involves NF-B activation (39). In keeping with a wider distribution of CaMKIV expression, removal of this gene results in strong phenotypic changes in the central nervous system (CNS) and in the periphery. Thus CaMKIV⫺/⫺ mice are deficient in two forms of synaptic plasticity: LTP in hippocampal CA1 neurons and a late phase of long-term depression in cerebellar Purkinje neurons (129). Despite impaired LTP and CREB activation, CaMKIV/Gr-deficient mice exhibit no obvious deficits in spatial learning and memory, although emotional memory, which is associated with CREB activation in amygdala and cortex, is significantly reduced (320). Moreover, CaMKIV null mice display locomotor defects consistent with a significant reduction in the number of mature Purkinje neurons and an immature development of Purkinje cells (258). Use of CaMKIV inhibitors or expression of a kinase-dead CaMKIV mutant blocks Ca2⫹-induced dendritic growth in cortical neurons, an effect that is strictly dependent on CREB phosphorylation (257). Outside the CNS, CaMKIV is highly expressed in the immune system and reproductive organs. Genetic deletion of the enzyme results in impaired positive selection in Physiol Rev • VOL
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thymocytes and defective Ca2⫹-dependent cytokine gene transcription in CD4⫹ T cells (12, 251) as well as reduced male and female fertility due to defective spermatogenesis and impaired follicular development and ovulation, respectively (325, 326). Nevertheless, the phenotype does not necessarily result from the lack of action on nuclear transcriptional effectors but could as well be related to the lack of phosphorylation of other substrates. Whereas phenotypic changes in neurons and memory CD4⫹ T cells are clearly associated with impaired CREB phosphorylation in mutant mice, CRE-dependent transcription is perfectly normal in germ cells of CaMKIV⫺/⫺ mice, suggesting that CaMKIV might use other targets in this cell type (325, 326). 2. Ca2⫹-dependent PKC isoenzymes To date, 11 closely related PKC isoenzymes have been described and classified into three subfamilies based on their domain structure and ability to respond to Ca2⫹ and DAG (226). The “conventional” PKC isoforms (␣, I, II, and ␥) are regulated by DAG, which binds the C1 domain, and by Ca2⫹, which binds the C2 domain. In contrast, the “novel” PKC isoforms (␦, , , and ) are not regulated by Ca2⫹ but respond to DAG. The molecular structure of the novel PKC isoforms is similar to that of the classical isoforms except for differences in the Ca2⫹ binding domain. The third group of PKC isoforms includes the “atypical” PKC isoforms (, /, and ), which are regulated neither by DAG nor Ca2⫹. Elevated concentrations of intracellular Ca2⫹ activate conventional PKC isoforms, recruiting the enzyme to the inner leaflet of the plasma membrane or the nuclear envelope within minutes. This process has been associated with changes in gene expression by two different mechanisms: 1) the first involves activation of IKK and nuclear translocation of activated NF-B to activate cytokine gene expression and T-cell proliferation (123, 309). The initial finding identified PKC- as responsible for the effect (183, 295). Ca2⫹-dependent conventional PKC ␣and -isoforms were shown to activate NF-B transcription as well (267, 290). A later study identified PKC-␣ action upstream of PKC- to activate the IKK complex and NF-B in T lymphocytes following TCR activation (310). 2) The second mechanism of Ca2⫹/PKC-mediated gene expression relates to increased nuclear activity of histone acetyltransferases (HAT). This mechanism has been described in epidermal cells where calcium induces epidermal cell differentiation and expression of several keratinocyte differentiation markers such as involucrin, filaggrin, loricrin, and transglutaminase (82). The process involves a dramatic increase in nuclear HAT activity and the specific acetylation of a subset of nuclear proteins. Calciuminduced HAT activity in epidermal cells is associated with
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CBP and P/CAF transcriptional coactivators, but only overexpression of P/CAF mimics the activation of the involucrin promoter and the specific nuclear acetylation. The effect of calcium on HAT activity is almost completely blocked by specific PKC inhibitors at concentrations that block only Ca2⫹/DAG-dependent “conventional” PKC isoenzymes, suggesting that “conventional” PKC isoforms may phosphorylate P/CAF to direct epidermal cell differentiation (154). Calcium-induced involucrin expression nevertheless seems to require a calcium-dependent tyrosine phosphorylation of PKC-␦ (78). Genetic ablation of the different “conventional” PKCs rendered a variety of phenotypes, suggesting diversified hierarchy in different biological functions. Thus PKC-␣⫺/⫺ mice showed cardiac hypercontractility, which protects against heart failure induced by pressure overload and rescues cardiomyopathy associated with overexpression of protein phosphatase 1 (35). B cells from PKC--deficient mice develop an immunodeficient phenotype that is related to their inability to activate IKK, degrade I-B, and upregulate NF-B-mediated induction of the prosurvival protein Bcl-xL (267, 290). Finally, mice deficient in PKC-␥ have a modified LTP of synaptic transmission in the hippocampus (1), and Purkinje cells show aberrant innervation from climbing fibers, while other aspects of the cerebellum including the morphology and excitatory synaptic transmission appear normal (152). B. Ca2ⴙ/Phosphatase-Regulated Transcription Pathways As important as phosphorylation events, Ca2⫹-dependent dephosphorylation of specific residues in key proteins within a given transcriptional network also induces
drastic changes in the activity of the network. Interestingly, activity-dependent phosphorylation and dephosphorylation are in some occasions coupled events that act on a particular protein or even on a particular phosphoresidue. In those cases, the specificities of the calcium signal to activate the two events alternatively require a fine tuning that so far is not well understood. Two major phosphatases, calcineurin, also termed protein phosphatase 2B (PP2B), and PP1, will be discussed in detail in this section. A summary of the different transcriptional networks regulated by these Ca2⫹-dependent phosphatases is shown in Figure 2. 1. Calcineurin-regulated gene expression Calcineurin is a Ca2⫹/calmodulin-activated serine/ threonine phosphatase, with a catalytic A subunit that binds calmodulin and a regulatory B subunit that binds calcium. Calcineurin conveys cytosolic Ca2⫹ signals to the nucleus, regulating the activity of at least three important transcription pathways involving NFAT, TORC, and myocyte enhancer factor-2 (MEF-2) proteins (for reviews, see Refs. 27, 30, 64, 255; see also sect. III) that control responses in the immune, nervous, and cardiovascular systems. Calcineurin may also interfere with gene expression through regulation of the intracellular concentration of free calcium by dephosphorylating phospholamban (219), the endogenous regulator of the SERCA2a calcium pump, ryanodine receptors (53), as well as the IP3R1 (43). Three genes encode the catalytic subunit of calcineurin in mammalian cells: CnA␣, CnA, and CnA␥. Genetic ablation of CnA␣ or CnA results in specific alterations of T-cell function, suggesting that the absence of one gene is not fully compensated by the others (37,
2⫹ FIG. 2. Molecular mechanisms of Ca -dependent transcription: activity-dependent phosphatases. Representation of the main transcriptional networks regulated by Ca2⫹/CaM-dependent protein phosphatases calcineurin and protein phosphatase 1 (PP1). For details about how these phosphatases regulate Ca2⫹-dependent transcription, see section IIB in the text.
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339). In support of distinct roles for the three proteins, lack of CnA␣ results in deficient T-cell response, while absence of CnA has profound effects on T-cell development, with fewer CD4/CD8 single positive cells and defective proliferative response. Furthermore, CnA-deficient mice show impaired cardiac hypertrophic response following pressure overload or isoproterenol infusion (38). The molecular basis of the functional specificity difference between ␣- and -isoforms is not fully understood, although it could be related to differential expression or distinct ability to interact with endogenous inhibitors. Thus the specific regulation of the CnA promoter by NFAT/GATA4 complexes was recently described (229), and several classes of endogenous inhibitors of calcineurin activity have been identified (see below). Compared with other mechanisms of Ca2⫹-dependent gene regulation, calcineurin has a particularly high affinity for Ca2⫹/calmodulin and is at least one order of magnitude more sensitive to Ca2⫹/calmodulin than is CaMKII. As a consequence, calcineurin responds to sustained, low-amplitude calcium transients, whereas CaMKdependent gene expression is used preferentially in response to transient, high-amplitude calcium spikes (84, 304). It was shown, however, that adequate calcium levels for calcineurin effects on gene expression may require calreticulin-mediated supply from the endoplasmic reticulum; embryonic lethality in calreticulin deficient mice is thus reversed by cardiac-specific overexpression of calcineurin (194). Furthermore, overexpression of activated calcineurin is associated with an intermediate phase of LTP in CA1 neurons of the hippocampus (324) and with defective long-term memory, evident in both a spatial task and a visual recognition task (199). Conversely, transient inhibition of calcineurin facilitates LTP, enhancing learning and strengthening short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks (199). Taken together, these data are consistent with the idea that endogenous calcineurin restrains LTP and memory. On the other hand, calcineurin B mutant mice have defects in axonal outgrowth but die at E10.0 due to failure to correctly pattern the developing vascular system (110). Calcineurin activity is regulated by its interaction with several endogenous proteins. The first inhibitor identified, AKAP79 (A-kinase anchoring protein-79), serves as a scaffold protein that anchors calcineurin to the membrane together with protein kinases A or C (160). Other inhibitors, such as Cabin1/Cain, A238L, and RCS (regulator of calmodulin signaling), function by blocking calcineurin binding to physiological substrates (170, 216, 250, 293), or by mimicking the interaction of calcineurin with its regulatory subunit calcineurin B as is the case of the CHP/p22 protein (184). More recently, a family of regulators of calcineurin (RCAN)-1 to -3 has been described (70, 157). RCAN-1, also known as calcipressin-1 Physiol Rev • VOL
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(Csp-1), MCIP-1, and Adapt78, is the protein product of the RCAN-1 gene previously known as DSCR1 because it is localized in the Down’s syndrome critical region (90, 98, 261). RCAN-1 is highly expressed in the CNS, immune system, heart, and skeletal muscle and was shown to interact physically and functionally with CnA, inhibiting both NFAT and MEF-2 signaling pathways (reviewed in Ref. 263). It has been proposed that RCAN-1 expression is regulated through a calcineurin-dependent mechanism that involves a cluster of NFAT binding sites in the promoter (reviewed in Ref. 263), indicating that RCAN-1 could function as a feedback inhibitor of calcineurin. Furthermore, it was demonstrated that glycogen synthase kinase-3 (GSK-3)-mediated phosphorylation of RCAN-1 reverses its effect on calcineurin signaling (127) and that RCAN-1 is repressed by the basic helix loop helix (bHLH) protein Hes-1 after Notch1 activation (198). On the other hand, RCAN-2, also known as Csp-2, MCIP-2, and ZAKI-4, is not regulated by calcium, but its expression in striated muscle is absolutely dependent on thyroid hormone levels (332). Work with RCAN⫺/⫺ or RCAN transgenic mice indicates that RCAN-mediated inhibition of calcineurin activity may represent a superimposed control of the calcium signal by finely tuning the calcineurin response to the calcium signal. Thus a high-threshold gene, such as Fas ligand (87), is kept silent under moderate TCR stimulation (265), and cardiac hypertrophy is blocked after calcineurin stimulation without repression of the induction of B-type natriuretic peptide (BNP), a lowthreshold calcineurin target gene in the heart (128). RCAN-1⫺/⫺ mice show premature cell death of Th1 lymphocytes during TCR-mediated proliferation due to aberrant expression of Fas ligand and enhanced responses in several models of cardiac hypertrophy (reviewed in Ref. 313). Conversely, targeted overexpression of RCAN-1, Cain/Cabin-1, or AKAP-79 in myocytes inhibits cardiac hypertrophy and preserves the systolic function (72, 128, 262). Calsarcins, a family of calcineurin-interacting proteins expressed specifically in striated muscle, also inhibit calcineurin (96). Calsarcin-1-deficient mice show an excess of slow muscle fibers and develop exaggerated hypertrophy in response to mechanical stress, which is associated with marked activation of a cardiac fetal gene program (95). The fact that calsarcin-1-deficient mice show induction of the fetal gene program but not cardiac hypertrophy in basal conditions and do not respond to other hypertrophic stimuli such as chronic isoproterenol administration or exercise, supports the concept that the calcineurin response to a given calcium signal is tuned to different thresholds by the specific action of calcineurin inhibitors that modulate the physiological or pathological response (265). Recently, an endogenous inhibitor of calcineurin, named Carabin, functions as a true feedback inhibitor
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since its expression is upregulated after TCR stimulation and calcium entry (235). Carabin induction is sensitive to inhibitors of calcineurin, indicating that Carabin constitutes part of a negative regulatory loop for the intracellular TCR signaling pathway. Knockdown of Carabin by short interfering RNA led to a significant enhancement of IL-2 production by antigen-specific T cells in vitro and in vivo (235). The most significant and best-characterized mechanisms by which calcineurin influences transcriptional networks involves dephosphorylation of NFAT and TORC and the activation of MEF-2 proteins (30, 65, 201, 274, 336). While in the first case the effect of calcineurin is a direct enzymatic action on NFAT and TORC proteins, in the second case, calcineurin regulates the activity of MEF-2 transcription factors by three different mechanisms that are discussed in detail in section IIIB. 2. PP1-regulated gene expression The calcium/calcineurin-dependent type 1 serine/ threonine protein phosphatase (PP1) holoenzyme consists of a highly conserved catalytic subunit and one or more regulatory subunits. Evidence accumulated in recent years indicates that PP1 activity is modulated largely by its interaction with ⬃70 different auxiliary proteins that target the enzyme to distinct subcellular compartments, conferring substrate specificity (21, 138). A subset of these interacting proteins are inhibitory proteins that block the catalytic activity of PP1. These include PP1 inhibitors 1 and 2, DARPP-32 (220, 331), as well as PNUTS and NIPP-1, two inhibitory subunits of PP1 that direct the nuclear targeting and retention of the enzyme, regulating PP1 nuclear activity (8, 178). Binding to PP1 and inhibition of its activity are regulated by PKA phosphorylation in both cases (28, 156), while calcineurin dephosphorylates inhibitor-1 blocking its activity which results in PP1 activation (89). PNUTS also binds to chromatin and enhances in vitro chromosome decondensation in a PP1dependent manner (171). Dephosphorylation of inhibitor 1 by other non-calcium-dependent phosphatases like PP2A should result in calcium-independent PP1 activation (89). A major role of PP1 activity in the nucleus is to dephosphorylate the transcription factor CREB (44) and terminate CREB-dependent gene expression. The mechanism involves the specific interaction of PP1 with HDAC1, which in turn recruits the phosphatase to the proximity of phosphoCREB, allowing its dephosphorylation (44). Conditional overexpression of PP1 protein inhibitor-1 in mice prolongs CREB phosphorylation and improves performance in an object recognition task (102). Strikingly, the improvement was observed only when mice were exposed to a protocol of distributed training with brief intertrial intervals, suggesting that the interference with Physiol Rev • VOL
the decay of CREB phosphorylation specifically mimicked the improved acquisition associated with long intertrial protocols (102). Furthermore, conditional inhibition of PP1 activity during training also improved the information retention for up to 6 wk after intensive training in the water maze test, supporting an active role of PP1 in memory decline. Overexpression of PP1 protein inhibitor-1 also resulted in extended autophosphorylation of CaMKII at Thr-286, a finding previously observed in vitro after local application of thiophosphorylated inhibitor-1 and associated with improved LTP at the Schaffer collateral-CA1 synapse (33). III. CALCIUM-DEPENDENT TRANSCRIPTIONAL NETWORKS A number of nuclear effectors whose action is regulated by changes in intracellular Ca2⫹ have been described over the years. The growing list includes proteins, which are targets of calcium-dependent posttranslational modifications as well as others, whose nuclear activity or presence is regulated by the interaction with Ca2⫹ or calcium binding proteins. This section reviews recent developments on the diversity of molecular mechanisms governing these calcium-sensitive transcriptional networks. A. The CREB/CBP/TORC Pathway It has long been accepted that Ca2⫹- and cAMPdependent pathways that control gene expression share many common players and points of cross-talk. Indeed, the accepted view involves several coincident steps, including the phosphorylation at Ser-133 of DNA-bound CREB dimers and recruitment of the coactivator paralogs CBP/p300 to trigger transcription of CRE-containing target genes (reviewed in Ref. 204). Recent studies have added new players and provided new steps into the process, some of which are strictly dependent on changes in intracellular Ca2⫹ levels. Binding of CREB as a dimer to the canonical CRE site (TGAGCTCA) has been considered the default start of the process. Work in Goodman’s laboratory using chromatin immunoprecipitation and in vivo genomic footprinting assays showed, however, that occupancy of CRE sites is regulated in a cell-specific manner and that the ability of CREB dimers to bind to a particular CRE represents an important component of gene regulation (48). In addition, core promoter configuration, including the presence of a TATA box motif and the vicinity to, and methylation state of consensus cAMP response elements near the promoter, are key factors in deciding the proportion of CREB target genes that will respond to cAMP in a given cell type (61, 342). Thus, before CREB is phosphorylated in response to
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a given stimulus in a particular cell type, genetic and epigenetic factors determine whether that cell will respond to the stimulus with an upregulation of CRE transcription just by allowing or preventing the CREB-controlled machinery to approach the specific promoter. Evidence has accumulated showing that Ser-133 CREB phosphorylation can occur through several kinases including PKA, PKC, mitogen-activated protein kinases (MAPKs; ERK and p38), CaMK, and CaMKK. As mentioned above, Ca2⫹/calcineurin-dependent activation of PP1 terminates CREB activation and stops CRE-dependent transcription (44). Both processes have been reviewed extensively (77, 108, 204). CBP/p300 recruitment to Ser-133 phosphoCREB is favored by signaling-dependent modifications of CBP by several kinases, including Ca2⫹- and CaMKIV-dependent phosphorylation of CBP at Ser-301, e.g., following NMDA receptor activation in cultured hippocampal neurons (135, 143). Nevertheless, serine to alanine mutation of residue 301 attenuates but does not block CREB/CBP-dependent transactivation, indicating that additional CaMKIV phosphorylation sites, particularly in the COOH terminal, or other kinases, including CaMKII, may as well participate in activity-dependent CBP induction. The Ca2⫹-dependent phosphorylation of CBP is thus an additional check-point controlling CREB/CBP-dependent transcription, although the mechanism by which phosphorylation of CBP affects its transactivating properties is not known. An intriguing possibility is that Ca2⫹-dependent CBP phosphorylation modifies its HAT activity, as previously shown for the P/CAF protein (154). In support of this mechanism, impaired chromatin acetylation in heterozygous CBP⫹/⫺ mice or after inducible expression in the forebrain of a mutant form of CBP that lacks HAT activity, CBP(HAT⫺/⫺), is related to long-term memory impairment that is reversed by pharmacological inhibition of histone deacetylases (5, 166). Overexpression of constitutively active CREB or treatment with rolipram, a phosphodiesterase-4 inhibitor that enhances CREB activation, partially rescues this phenotype (5, 34). Nonetheless, CREB phosphorylation alone is not a reliable predictor of target gene activation, and additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter. It has been shown that calcium signals destabilize the CREB-CBP complex through secondary phosphorylation events on CREB (164) and that the DNA binding/dimerization domain (bZIP) in CREB mediates transcriptional response to both calcium influx and cAMP (278). In this case, the bZIP appears to contribute significantly to induction of CREB activity in response to membrane depolarizing signals, implicating this domain in CREB association with a calcium-regulated coactivator. Indeed, search for proteins able to interact with CREB and to induce CREB activity identified a conserved family of coactivators, designated Physiol Rev • VOL
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TORCs, for transducers of regulated CREB activity, that enhances CRE-dependent transcription via a phosphorylation-independent interaction with the bZIP DNA binding/dimerization domain of CREB. TORC recruitment does not appear to modulate CREB DNA binding activity, but rather enhances the interaction between the glutamine-rich transactivation domain of CREB and the TAFII130 protein, a component of the TFIID complex, following TORC recruitment to the promoter (61, 145). The three TORC family members share an NH2-terminal coiled-coil domain that associates as a tetramer with the bZIP domain of CREB. Contrary to CBP, expression levels of TORC proteins are very low in the cell. In basal unstimulated conditions, TORC proteins are localized mainly in the cytosol, which makes it difficult to understand their crucial role as limiting factors for CREB transcription. Later studies from the two laboratories involved in the identification of TORC proteins defined a “signaling module” that mediates calcium- and cAMPdependent, phosphorylation-independent activation of the CREB transcription factor. The pathway involves the calcium-regulated phosphatase calcineurin and the Ser/ Thr kinase SIK2, both of which associate with TORC2 in pancreatic islet cells. Under resting conditions, TORC2 is sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins. Following glucose and gut hormone stimulation, calcium influx increases calcineurin activity triggering TORC2 dephosphorylation, its release from the interaction with 14-3-3 proteins, and its nuclear translocation. Concomitant stimulation of the cAMP pathway after glucose and hormone action inhibits SIK2 kinase activity, reducing TORC2 phosphorylation. Through this mechanism, the concerted action of a phosphatase/kinase module connects two signaling pathways in response to nutrient and hormonal cues (30, 274). In a recent report, Montminy’s group shows that hormonal- and energy-sensing pathways converge on the coactivator TORC2 to modulate glucose output. Under fasting conditions or after glucagon administration, TORC2 thus translocates to the nucleus and enhances CREB-dependent transcription. Conversely, signals that activate the energy-sensing kinase AMPK inhibit hepatic gluconeogenesis by promoting TORC2 phosphorylation and nuclear export. These results suggest that fasting hyperglycemia associated with elevated gluconeogenesis in type 2 diabetes could potentially be treated with compounds that enhance TORC2 phosphorylation (162). A key role for TORC proteins in muscle cells has been described to induce the expression of PGC-1␣, a master regulator of mitochondrial biogenesis and energy metabolism (329). Finally, also in line with the phosphorylation-independent regulation of CREB activity, a Ca2⫹-dependent interaction between transcriptional repressor DREAM and CREB or phosphoCREB regulates the accessibility of
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CBP to the KID domain in CREB, and so compromises CRE transcription (174). This mechanism, which is described in detail later in this review, constitutes together with the Ca2⫹-dependent modulation by TORC proteins a new possibility to module CREB activity independently of its phosphorylation state. B. The MEF-2 Crossroad of Ca2ⴙ Regulation The MEF-2 family of myogenic transcription factors (MEF-2A to D) is an important determinant in muscle differentiation and T-cell activation through the transcriptional control of specific target genes (31, 336). It was found that MEF-2A and MEF-2C are highly expressed also in postmitotic neurons of the cerebellum and the cerebral cortex, respectively, and that MEF-2 expression is essential for the survival of these neurons (200). Transcriptional actions of MEF-2 proteins are regulated by a variety of mechanisms. In resting conditions, MEF-2 proteins are bound to DNA as part of a repressor complex that includes histone deacetylases and calmodulin binding proteins among others (189). HDAC4 and -5 interact with the so-called MEF-2 domain, located next to the MADS box in the NH2 terminal of MEF-2 proteins (189, 215, 318), resulting in the repression of MEF-2 transcriptional activation, e.g., of the c-jun promoter (318). MEF-2B and -D are normally sequestered by cabin1 (190) or the MEF-2 interacting transcriptional repressor (MITR) (285) in multiprotein complexes together with HDAC1. Cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase to repress MEF2 transcriptional activity (149, 162). As a result, transcription of target genes like nur77 is also repressed (337), and myoblast differentiation is blocked (190). HDAC4, cabin1, and MITR are Ca2⫹-CaM binding proteins that bind calmodulin with the same domain responsible for binding of MEF-2 proteins (337, 338). Thus activity-dependent increase in nuclear Ca2⫹/CaM complexes after stimulation releases MEF-2 proteins from the repressor complex (337, 338). This Ca2⫹-dependent mechanism is partially counteracted in the case of MEF-2D by increased cAMP levels (26). In addition, Ca2⫹-dependent phosphorylation of the MEF-2 domain by CaMKI and CaMKIV disrupts HDACmediated repression and releases MEF-2 (189, 190). Both CaMKI and CaMKIV can phosphorylate HDAC4 and -5, creating a phosphodomain that binds to 14-3-3 proteins and mediates shuttling of HDACs from the nucleus to the cytosol as well as releases repression from MEF-2 (205, 206). Noteworthy, a negative-feedback loop between MEF-2 proteins and HDAC9 has been recently disclosed by showing that HDAC9 is a direct transcriptional target of MEF-2 in myocytes, where HDAC9 associates with MEF2 proteins to suppress their transcriptional activity (117). Physiol Rev • VOL
Activation of nonrepressed MEF-2 proteins is also a Ca2⫹-dependent process, for which two major mechanisms have been proposed. First, as shown in cerebellar neurons by Greenberg’s group, calcium influx through voltage-sensitive calcium channels triggers activation of MKK6-p38 MAPK resulting in the phosphorylation of Ser387 located in the transactivation domain of MEF-2C (202). Second, the Ca2⫹/CaM-dependent phosphatase calcineurin activates MEF-2 through a posttranscriptional mechanism that either increases its DNA binding activity in cerebellar granules (201) or triggers interaction of MEF-2 and NFAT proteins and recruitment of CBP to these complexes in T lymphocytes (32, 336). Ca2⫹/CaMdependent signaling thus prevents formation of the MEF2/HDAC complexes, induces nuclear export of class II HDACs, activates MEF-2-dependent transcription, and as a result stimulates cytokine expression, myogenesis, and neuronal survival. An integrated view of different Ca2⫹dependent mechanisms regulating MEF-2 transcriptional activity is shown in Figure 3. Abrogation of MEF-2C by homologous recombination in mice leads to early embryonic lethality at E9.5 due to cardiac defects (182). Specifically, mutant mice lacking the MEF-2C gene show a severely hypoplastic right ventricular chamber and outflow tract, suggesting that these cardiogenic regulatory factors may act in a common pathway for development of the anterior heart field and its derivatives. It was recently shown that expression of the BOP nucleoprotein in the developing heart depends on the direct MEF-2C binding to a MEF-2-response element in the Bop promoter. Consistent with this, mice deficient in the BOP transcriptional activity reproduce the MEF-2C⫺/⫺ phenotype. MEF-2C is thus necessary and sufficient to recapitulate endogenous BOP expression in the anterior heart field and its cardiac derivatives during mouse development. The Bop promoter also directs transcription in the skeletal muscle lineage, but only cardiac expression is dependent on MEF-2C. These findings identify Bop as an essential downstream effector gene of MEF-2C in the developing heart and reveal a transcriptional cascade involved in development of the anterior heart field and its derivatives (246). Although MEF-2C is the only family member shown to have a role in early heart formation, MEF-2A is the predominant mef2 gene product expressed in postnatal cardiac muscle. In accordance with this, most mice lacking MEF-2A die suddenly within the first week of life and exhibit pronounced dilation of the right ventricle, myofibrillar fragmentation, mitochondrial disorganization, and activation of a fetal cardiac gene program (224). The few MEF-2A⫺/⫺ mice that survive to adulthood show a deficiency in cardiac mitochondria and susceptibility to sudden death. These MEF-2A-mutant mouse phenotypes reveal an essential role for MEF-2A in maintenance of mitochondrial content and cytoarchitectural integrity in
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2⫹ FIG. 3. Multiple Ca -dependent pathways control MEF-2-dependent transcription. See section IIIB in the text for details.
postnatal cardiac myocytes and show that other MEF-2 isoforms cannot fully support these activities. Surprisingly, MEF-2 transcriptional activity, revealed by the expression of a MEF-2-dependent reporter transgene, is enhanced in the hearts of MEF-2A-mutant mice, reflecting the transcriptional activation of residual MEF-2D. The MEF-2A-mutant mouse phenotype clearly differs from that of MEF-2C mutants, which die at E9.5 from severe cardiovascular abnormalities. In light of the overlapping expression patterns and similar DNA-binding activities of the four vertebrate Mef2 gene products, it is likely that these proteins have distinct as well as partially redundant functions. The generation of conditional MEF-2CloxP/loxP mice recently showed that myocardial-specific removal of MEF-2C results in viable offspring, demonstrating that whereas MEF-2C is required for early development of the heart, it is not necessary for the formation of the heart after looping morphogenesis (316). As MEF-2C is also highly expressed in postmitotic neurons, smooth muscle cells, and skeletal muscle precursors, MEF-2CloxP/loxP mice could serve as a useful tool for dissecting the role of MEF-2C in these various cell types. C. The NFAT Family of Transcription Factors The NFAT family of transcription factors, NFATc1 to -c4 and NFAT5, also known as TonEBP, are proteins evolutionarily related to the Rel/NF-B family. Dephosphorylation of NFAT proteins by calcineurin exposes their nuclear localization signal and allows nuclear translocation. Once in the nucleus, NFAT proteins bind DNA, alone or in complexes with other nucleoproteins, e.g., the Physiol Rev • VOL
Fos-Jun heterodimers, to activate transcription of specific sets of genes depending on the cell type (reviewed in Refs. 130, 255). The process is terminated by casein kinase I or the sequential action of PKA and GSK-3, constitutive NFAT kinases that rephosphorylate NFAT, exporting the protein back to the cytosol (24, 111). In addition, MAPKs p38 and JNK are inducible NFAT kinases, which may couple the termination of the calcineurin cascade with different signaling pathways, simultaneously conferring an additional specificity since p38 and JNK show distinct affinities for the different NFAT family members (57, 333). Encoded in the Down’s syndrome critical region, the dual-specificity tyrosine-phosphorylation regulated kinases (DYRK) 1A and 2 are physiological negative regulators of NFAT activation and have been implicated in the regulation of NFAT phosphorylation (15, 116). DYRK1A, which is localized in the nucleus, acts as a priming kinase that enables additional phosphorylation of NFAT by CK1 and GSK-3 leading to NFAT inactivation (15, 116). DYRK2, which is localized in the cytoplasm, functions as a “maintenance” kinase that sustains the phosphorylation state of cytoplasmic NFAT in resting cells (116). Selective activation and action of export kinases therefore explain how individual NFAT proteins might be differentially regulated in a single cell type in response to calcium stimulation. The process as a whole is extremely rapid, giving NFAT proteins the remarkable ability to sense dynamic changes in intracellular Ca2⫹ levels and frequencies of Ca2⫹ oscillations (84). Ca2⫹-dependent regulation of the calcineurin/NFAT transcriptional network encompasses both activation and repression of several target genes. Gene profiling shows that activation follows
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the coordinated action of NFAT:AP-1 complexes, whereas NFAT in the absence of AP-1 recruits corepressors and silences the expression of genes (196). Indeed, it was more recently suggested that repression of CDK4 by NFAT involves the recruitment of histone deacetylases to a site just 3⬘ of the transcription start site of the CDK4 gene (18). Genetic ablation of single NFAT genes generally results in mild phenotypes, indicating a certain degree of redundancy. There are, nevertheless, notable exceptions: 1) mice with a deletion in the NFATc1 gene show impaired formation of cardiac valves and septa, suggesting a role for calcineurin/NFATc1 in the cardiac endothelium during cardiac morphogenesis (71, 253) acting together with GATA5 to control the expression of endothelin-1 (225), and to direct the differentiation of the Th2 response (330, 335); and 2) deletion of NFATc2 alone moderately increases cytokine production by Th2 and mast cells (284, 312), whereas for instance, deletion of NFATc3 does not alter cytokine expression (234). In most cases, however, prominent phenotypes are observed only when two or more NFAT proteins are lacking. Deletion of both NFATc1 and -c2 is thus required for important loss of cytokine production in T cells (242); deletion of both NFATc2 and NFATc3 results in preferential Th2 cytokine production (254). Deletion of both NFATc3 and NFATc4 isoforms results in serious defects in sensory axon projections, which are mimicked by calcineurin inhibition during embryonic development; these mice die in utero due to failure of normal vascular patterning. Death is the result of derepression of the vascular endothelial growth factor (VEGF) gene, and due to the growth of vesicles into the nervous system and somites (110, 151). Finally, deletion of three members, NFATc2, -c3, and -c4, is required to observe striking defects in axonal outgrowth in the central and peripheral nervous systems. Cultured primary neurons, sensory or commissural, from these triple knockout mice are unable to respond to neurotrophins or netrin-1 with efficient axonal outgrowth. These data indicate that the ability of embryonic axons to respond to growth factors with rapid outgrowth requires activation of a calcineurin/NFAT pathway, while survival effects are independent (112). These results are in line with the aberrant sensory behavior described in Caenorhabditis elegans bearing a loss-of-function mutation in TAX-6, a calcineurin catalytic subunit (168). Also indicative of functional redundancy, overexpression of constitutively active versions of NFATc1 and NFATc2, in which a large fraction of the phosphorylated serines have been mutated to alanines to mimic the dephosphorylated form, elicit a similar increase in expression of most cytokine genes (218). Finally, overexpression of a constitutive active form of NFATc4 results in cardiac hypertrophy and eventual heart failure, a phenotype observed also after expression of activated calcineurin (217). Physiol Rev • VOL
D. The DREAM/KChIP Family of Ca2ⴙ-Sensitive Transcriptional Repressors DREAM (downstream responsive element antagonist modulator), also termed KChIP-3 (potassium channel interacting protein-3) or calsenilin, is a multifunctional protein of the DREAM/KChIP subfamily of calcium sensors (KChIP-1 to -4) (11, 42, 46). Depending on the cell type and the physiological conditions, DREAM shows multiple subcellular localizations, in the nucleus, cytosol, or cell membrane (Fig. 4). DREAM is widely expressed in the brain, in particular in sensory neurons where it has a predominantly nuclear localization (Fig. 4). All four members of the family are structurally and functionally related (185), and they are coexpressed in many different brain areas (Fig. 5), as well as in other tissues including the
FIG. 4. Subcellular distribution of DREAM/KChIP3. A: immunocytochemistry with specific antibodies for DREAM showing the preferential nuclear localization of endogenous DREAM protein in freshly isolated mouse sensory neurons. Note absence of staining in the nucleolar compartment and weak signal in cytoplasm. B: confocal image showing the preferential membrane localization of the DREAM-EGFP signal after overexpression together with the interactive protein Kv4.2 potassium channel. [Adapted from Ruiz-Gomez et al. (264a).]
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FIG. 5. Differential expression of DREAM/KChIP mRNA in different brain areas. Analysis was performed by quantitative real-time PCR using specific TaqMan probes and primers for each of the four KChIPs, 1-4. Coexpression of two or more KChIPs is observed in most areas analyzed.
immune system, thyroid gland, and reproductive organs (11, 42, 46, 271). All four DREAM/KChIP family members share the unique property to bind as homo- or heterotetramers to a specific site in the DNA, the DRE site, and repress transcription in a Ca2⫹-dependent manner (46, 66, 185, 232). Mutation within any of the three functional calcium binding EF-hand motifs in DREAM results in mutant proteins, EFmDREAMs, that retain the ability to bind the DRE sequence and to repress transcription, but are insensitive to calcium and remain bound to the DRE site during activity-dependent stimulation, blocking Ca2⫹dependent derepression (46). Since DNA binding and re-
pressor function is dependent on DREAM/KChIP heterotetramers, EFmDREAM proteins function as dominant active mutants of endogenous KChIP proteins during basal or Ca2⫹-induced cell activation (107, 271). A scheme depicting the mechanism of Ca2⫹-insensitive repression by EFmDREAM is shown in Figure 6. In addition, derepression of DRE-dependent transcription is regulated by PKA or PI 3-kinase activation (173, 270). cAMP-dependent derepression is associated with specific protein-protein interactions between DREAM and ␣- or -CREM, two nuclear effectors of the transcriptional actions of cAMP (173). This interaction requires two leucine-charged resi-
FIG. 6. DREAM-mediated transcriptional repression. A: basal repression of DREAM target genes upon binding of DREAM/KChIP heterotetramers to the DRE site. B: stimulated derepression of DREAM-mediated repression by different stimuli including Ca2⫹ (i), DREAM phosphorylation (ii), or the interaction of DREAM with other nucleoproteins such as ␣CREM (iii). Once DREAM is detached from the DRE site, trancription of a given target gene will proceed driven by the specific combination of enhancers (E) and silencers (S) present in the promoter region. C: blockage of Ca2⫹-mediated derepression by the presence of EFmDREAM within the DREAM/ KChIP heterotetramer bound to the DRE site.
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due rich domains (LCDs) present in DREAM and ␣-/CREM (173). The LCD motif was first described in nuclear coactivators (NCoA-1, p/CIP) and corepressors (NCoR, SMRT) and has been implicated in protein-protein interactions with nuclear hormone receptors and CBP (136, 172, 308). The presence of functional LCDs within the DREAM protein may thus allow DREAM to interact with several other nucleoproteins to regulate transcriptional events not directly related to the presence of DRE sites. Indeed, we have reported that a LCD-dependent DREAM/ CREB interaction displaces CREB from CRE sites and prevents CBP recruitment to phosphoCREB, which results in a reduction of CRE-dependent transcription without direct binding of DREAM to the CRE site (174). The DREAM-CREB interaction is Ca2⫹ dependent, and Ca2⫹insensitive DREAM mutants (EFmDREAM) also act as dominant repressors of Ca2⫹-dependent CREB-mediated transcription (174). In addition, LCD- and Ca2⫹-independent protein-protein interactions between DREAM and several other nucleoproteins have been reported (259, 275). DREAM was identified through its binding to the DRE in the proximal promoter of the prodynorphin gene (46, 47). Consistent with a role for DREAM in the regulation of the prodynorphin gene, DREAM⫺/⫺ mice show upregulation of prodynorphin expression in spinal cord, which results in a hypoalgesic phenotype (56). Curiously, genetic ablation of the functionally related neuronal calcium sensor-1 gene in C. elegans results in worms with defects in learning and memory for isothermal sensitivity (105). Nevertheless, except for the modified noxious sensitivity and an anomalous response to chronic cannabinoid administration (56), no other phenotypic changes have been described in DREAM⫺/⫺ mice, supporting the idea that functional redundancy between members of the family compensates for the genetic ablation of DREAM/ KChIP-3. To overcome this problem, an EFmDREAM dominant active mutant was used in conventional transgenesis to block activity-dependent DREAM-KChIP-mediated derepression and to address the analysis of the physiological significance of this group of proteins. In two recent reports, overexpression of EFmDREAM in T cells or in neurons has dramatic effects on the response to TCR engagement or to extracellular depolarizing conditions, respectively (107, 271). In T lymphocytes, endogenous DREAM expression is downregulated in response to TCR stimulation, and overexpression of EFmDREAM results in reduced proliferative response after polyclonal TCR activation or following an antigen-specific response (271). The phenotype could be associated with decreased expression of several Th1 and Th2-specific cytokine genes including IL-2, IL-4, and interferon (IFN)-␥, suggesting DREAM as a new target for the development of immunosupressant drugs (271). Overexpression of EFmDREAM in the cerebellum of transgenic mice significantly reduces Physiol Rev • VOL
mRNA and protein levels of the sodium/calcium exchanger-3 (NCX3) without modifying the expression of NCX1 and NCX2. Reduced NCX3 protein levels in cerebellar granules results in increased levels of free cytosolic Ca2⫹, making transgenic neurons more vulnerable to increased Ca2⫹ influx following partial opening of voltage-gated plasma membrane Ca2⫹ channels induced by increasing K⫹ in the culture medium. Lentiviral-mediated overexpression of the NCX3 exchanger in cerebellar transgenic granules restores normal Ca2⫹ homeostasis, indicating that the phenotypic change in these transgenic neurons is related exclusively to the downregulation of NCX3 by DREAM (107). DREAM/KChIPs are the only EF-hand calcium sensors so far known to bind specifically to DNA and directly regulate transcription in a Ca2⫹-dependent manner. Recently, however, a novel DNA binding protein called Freud-1 (5⬘ repressor element under dual repression binding protein-1) was reported to bind to the FRE site in the proximal promoter of the serotonin 1A receptor gene and to mediate its Ca2⫹-dependent repression (233). Freud-1 is evolutionarily conserved and has two DM-14 basic repeats, a predicted helix-loop-helix DNA binding domain, and a C2 region, calcium/phospholipids binding domain, similar to those found in conventional PKC isoenzymes. An intact C2 domain is required for Freud-1 to mediate derepression, whereas treatment with inhibitors of CaM or CaMKs reversed Ca2⫹-mediated Freud-1 inhibition, suggesting an additional regulatory mechanism that needs further investigation. Freud-1 thus represents a novel calcium-regulated repressor that, at least in transient transfection experiments, negatively regulates basal 5-HT1A receptor expression. E. The NF-B /I-B Couple NF-B is expressed in nearly all cell types and is implicated in the regulation of numerous genes mediating immune, inflammatory, and stress responses (for reviews, see Refs. 104, 147). NF-B is a heterodimer of p65 (RelA) with p50 or p52. This heterodimer is anchored by a group of proteins termed IB, which retain NF-B in the cytosol by masking its nuclear localization signal (25). Following site-specific IB hyperphosphorylation at S32 and S36 by two IB kinases, IKK␣ and IKK (79, 211), the inhibitor molecule becomes susceptible to site-specific ubiquitination and subsequent degradation by the proteasome complex (36, 273). This releases NF-B, allowing nuclear translocation. In addition, more recent studies in T lymphocytes and neurons identified CaMKII as an activator of NF-B. In response to T-cell receptor (TCR) activation, nuclear translocation of NF-B can be blocked by inhibitors of CaM or CaMK, or mimicked by overexpression of a constitutively active form of CaMKII (141). In basal conditions in neurons, the p65:p50 NF-B form is selec-
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tively localized at synapses. Following membrane depolarization in neurons there is an increase in NF-B DNA binding that is inhibited by blockers of synaptic transmission, voltage-dependent Ca2⫹ channel inhibitors, or antagonists of glutamate receptors (207). In addition, in NF-B p65⫺/⫺ mice, the study reveals a Ca2⫹-dependent role of NF-B in learning and memory, which is not due to gross differences in motivation, perceptual, or motor skills. F. Novel Mechanisms Associated With Ca2ⴙ-Dependent Gene Expression Search for new Ca2⫹-sensitive transcriptional effectors using a transactivator trap strategy led to the identification of CREST (for calcium responsive transactivator) from a cerebral cortex cDNA library (4). Overexpression of CREST as a Gal4 fusion protein drives expression of an UAS reporter in nondifferentiated embryonic rat cortical neurons in culture in response to potassium depolarization or bath application of glutamate, two well-characterized stimuli that increase intracellular calcium concentration and trigger a variety of cellular responses including dendrite outgrowth and neuronal death (122). CREST does not bind directly to DNA; therefore, it must associate with other nucleoproteins to activate transcription. Indeed, CREST has been shown to interact with CBP through its last nine COOH-terminal amino acids, a mechanism that could explain CREST-mediated dendritic growth, a process associated with CREB phosphorylation after Ca2⫹/cAMP neuronal stimulation (reviewed in Ref. 256). Interestingly, CREST⫺/⫺ mice show a reduction in dendritic growth and branching that is specific for the basal rather than apical dendrites in cortical pyramidal neurons (4). Given the pleiotropic effects of the CREB/ CBP/TORC transcriptional network, future studies should identify other CREST interactors in the nucleus responsible for this specific action on dentritic maturation. In addition, CREST homodimerization has been proposed to be necessary to block an inhibitory domain located next to a nuclear localization signal in the COOH-terminal 150 amino acids of the protein (248). A number of interesting questions about CREST can be raised: 1) which are the final gene targets of CREST that mediate the effect on dendrite growth; 2) 80% of CREST⫺/⫺ mice die before adulthood within the second or third week after birth, indicating that CREST may be relevant for additional biological effects; and 3) how calcium signals actually activate CREST. This is an important issue, since no calcium binding motifs have been observed in CREST and not even its interaction with CBP has been shown to be induced upon neuronal depolarization (4). Cleavage of the COOH-terminal end of voltagegated calcium channels (VGCCs) is a well-known phePhysiol Rev • VOL
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nomena, and the cleaved fragments have been implicated in regulating channel activity by reducing Ca2⫹ influx (142). Recently, however, the COOH-terminal intracellular fragment of the Cav1.2 subunit of the L-type VGCC, named, calcium channel-associated transcriptional regulator (CCAT), was shown to localize in the nuclei of GABAergic inhibitory interneurons in the cortex and hippocampus and to regulate transcription of selective target genes (106, 222). Importantly, the nuclear pool of CCAT is rapidly extruded in response to calcium entry following neuronal membrane depolarization (106); CCAT-regulated gene expression is sensitive to calcium stimulation. Whether CCAT is found in the nuclei of other cell types that express L-type channels and regulates gene expression in nonneuronal cells is not known. Transcriptional regulation by CCAT does not seem to involve direct interaction with DNA but rather involves interaction with other nucleoproteins, such as p54(nrb)/ NonO (nuclear RNA- and DNA-binding protein of 54 kDa, also known as Non-POU domain-containing octamerbinding protein) (264). Since other Cav subunits have been reported to be cleaved in neurons (126, 167, 322) and one of them, the Cav 2.1 subunit, generates a COOH-terminal fragment that has been localized to Purkinje cell nuclei (163), additional effectors to be described may share with CCAT this novel Ca2⫹-dependent mechanism to control gene expression. IV. CALCIUM-DEPENDENT PROTEIN-PROTEIN INTERACTIONS THAT MODULATE GENE EXPRESSION Like DREAM, other calcium sensors, mainly CaM but also S-100 and calreticulin, are multifunctional proteins able to interact with various nuclear targets after Ca2⫹ binding to regulate the activity of transcription factors or enzymes that influence chromatin structure to eventually change gene expression. From the viewpoint of control of transcriptional networks by nuclear Ca2⫹, two types of interactions will be discussed because of their significance: 1) the interaction between Ca2⫹-bound calcium sensors and transcription factors of the bHLH (63) and the nuclear receptors superfamilies (40, 74) and Sox proteins (14) and 2) the Ca2⫹-mediated changes in chromatin structure. A. Ca2ⴙ Sensors in the Nucleus CaM, a small acidic protein, is the prototypic calcium sensor (reviewed in Ref. 129a). CaM contains four EFhand Ca2⫹-binding motifs, distributed in pairs embedded within two separate globular regions at the NH2 and COOH termini. A flexible central helix completes the
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characteristic dumbbell-shaped structure (289). S-100 proteins are also EF-hand proteins able to interact in a Ca2⫹-dependent manner with many targets, some of which are common with CaM. Of particular importance here is the property of both CaM and S-100 proteins to establish electrostatic interactions with the basic DNAbinding domain of class I bHLH transcription factors (63, 231). Following interaction, binding to DNA is blocked, and as a result, transcriptional activity is lost. In addition, binding of Ca2⫹-loaded CaM or S100 proteins to bHLH proteins may prevent posttranslational modifications, affecting their transactivation potential (22) or block their interactions with components of the transcriptional machinery such as HATs, HDACs, or other nuclear proteins including pRB, Notch, and Mos (177). Interaction of bHLH proteins with the Ca2⫹/calcium sensor complex thus results in profound changes in their transcriptional activity through a variety of mechanisms. bHLH proteins are a family of numerous nucleoproteins, widely expressed in various organs, where they are involved in the control of cell growth and differentiation (203). The consequences of bHLH protein regulation by calcium sensors are potentially very significant during neurogenesis, hematopoiesis, and myogenesis. Studies so far are limited to in vitro analysis or to the use of transfected cells. Genetically modified murine models that demonstrate the physiological consequences of interactions between bHLH proteins and calcium sensors for the control of gene expression are, however, still missing. Although genetic ablation of Neuro2D, a calcium-sensitive bHLH protein, results in incorrect patterning and lack of synaptic maturation of thalamocortical projections (144), knock-in mice expressing a Ca2⫹-insensitive mutant of Neuro2D should be required to directly relate the potential Ca2⫹ effect on the thalamocortical development. Calreticulin, a calcium-binding protein initially localized predominantly within the ER, interacts with the DNA-binding domain of several nuclear receptors, including glucocorticoid, androgen, retinoic acid, and vitamin D receptors. As a result of these interactions, calreticulin inhibits nuclear receptor-mediated transcription (40, 74). In addition, calreticulin mediates Ca2⫹-dependent nuclear export of glucocorticoid receptors (131, 132). Calreticulin thus reduces the accessibility of nuclear receptors to regulate transcription through two mechanisms, blocking the binding to DNA and reducing the presence of the receptor in the nucleus. Deletion of the NH2-terminal signal sequence of calreticulin appears to eliminate its effects on glucocorticoid receptor transactivation (214), but does not influence its function as a nuclear export factor for the glucocorticoid receptor (75). Finally, nuclear import of transcription factors can also be regulated by CaM, as recently described for Sox proteins. Sox (Sry-related HMG box) is a large family of transcription factors that activate gene expression by Physiol Rev • VOL
binding to DNA in a sequence-specific manner through their HMG box and by interacting with specific partner proteins (for a recent review, see Ref. 133). Interaction of Ca2⫹-bound CaM with the HMG domain of Sox9, an early embryonically expressed member of the family that regulates chondrogenesis, testis formation, and neural crest development (133), blocks its nuclear import and consequent transcriptional activity (14). Missense mutations at the Sox9 HMG box affect CaM interaction and result in campomelic dysplasia/autosomal sex reversal (CD/SRA), a severe bone malformation syndrome in which most XY individuals show male-to-female sex reversal (14). Calcium regulation of Sox9 activity is thus crucial for its biological effects. Since the HMG box is common to all members of the Sox family, it can be predicted that calcium plays a major role during organ development by selectively regulating the activity of specific Sox proteins. B. Ca2ⴙ-Dependent Changes in Chromatin Structure Ca2⫹-dependent enzymes not only modify the activity of specific transcriptional networks but also act on chromatin-associated proteins, histones (H) and high mobility group (HMG) proteins, to evoke selective modifications in the nucleosomal environment that encompass specific genes to either expose or mask their regulatory sites to transcriptional regulators. An example is the correlation between c-fos induction and the increased sensitivity to DNaseI of the c-fos gene (91), which is related to phosphorylation of histone H3 and HMG proteins (153). Histones are essential components for the arrangement of the nucleosomes, and posttranslational modifications, including acetylation, phosphorylation, methylation, and ADP-ribosylation, have profound effects on chromatin structure and on gene expression. The HMG proteins are non-histone chromosomal proteins of low molecular mass, fundamental for stabilizing the enhanceosome at promoter regions and mediating transcriptional elongation (80). Because of their critical role in transcription, they are also called architectural transcription factors, although they do not make sequence-specific contact with the DNA. Of the posttranslational modifications, phosphorylation and acetylation/deacetylation are the best characterized in terms of their association with activity-dependent changes in chromatin structure. Early work from Schulman’s laboratory (323) reported the specific phosphorylation of histone H3, but not other histones, and of HMG protein-17 in isolated nuclei from untreated cells in response to an increase in external Ca2⫹ in vitro. The precise mechanism by which phosphorylation of these nucleosomal proteins facilitates transcription is not known; however, it was elegantly demonstrated that phosphory-
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lation follows the hyperacetylation and decreases methylation on the same NH2-terminal histone tails (58, 266). On this basis, phosphorylation was proposed to stabilize an open conformation, perhaps blocking access of transcriptional corepressors associated with HDACs and DNA methyltransferases. An important issue has been to identify the kinase(s) responsible for histone phosphorylation leading to transcriptional activation. Ca2⫹/CaM-dependent phosphorylation of histone H3 was reported first, suggesting the involvement of a nuclear CaMK (317). More recently, the mitogen- and stress-activated kinases, MSK1 and MSK2, two effector kinases downstream of ERK and p38, were demonstrated to be responsible for the H3 and HMG protein 14 phosphorylation associated with immediate early gene activation (283, 302) and cytokine gene expression during inflammation (266). Notably, MSK kinases are also responsible for the direct activation of NF-B p65 subunit and CREB (73, 314). Several Ca2⫹dependent kinases thus phosphorylate histone H3 and specific transcription factors to coordinately activate transcriptional networks that participate in the immediate early or the inflammatory responses. The system is reset by the calcineurin-dependent nuclear protein phosphatase 1, which has been implicated in H3 dephosphorylation (49). Phosphorylation of histones and HMG proteins has been studied mainly in vitro and in cultured cells. Nonetheless, two recent reports suggest a role in vivo, showing that a light pulse during the subjective nighttime stimulates MSK1 phosphorylation of H3 (41, 67) in hypothalamic neurons of the suprachiasmatic nucleus, a major central circadian clock. The effect of light is specific, and the kinetics of H3 phosphorylation parallel the early induction of c-fos and mPer1 (the mouse ortholog of the Drosophila gene period) in the same neuron (67). Moreover, systemic blockage of GABAB receptors with baclofen prevents light-induced H3 phosphorylation and c-fos and mPer1 gene expression (67). These results correlate well with circadian variation in phosphoCREB in suprachiasmatic neurons and light-induced upregulation of CRE-dependent transcription during the subjective nighttime (227). The architectural transcription factor HMG-I(Y) regulates expression of the rhodopsin gene in terminally differentiated retinal photoreceptors (50). The mechanism involves the interaction of HMG-I(Y) with the Crx homeoprotein, which participates in the circadian regulation of rhodopsin gene expression (50). In addition, phosphorylation of HMG-I(Y) by PKC also regulates its activity as reported in tumoral cell lines (20). Acetylation/deacetylation, linked predominantly to activation and repression, respectively, are to date probably the most extensively studied posttranslational histone modifications. It is commonly accepted that acetylation partially neutralizes the positive charge of histones, reducing their affinity for DNA, thereby creating an open Physiol Rev • VOL
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structure that permits the access of other proteins to the DNA. The reverse effect is achieved after histone deacetylation. Activity-dependent changes in histone acetyltransferase activity have been presented earlier in this review. Therefore, we now present recent studies focused on activity-dependent mechanisms that modify the activity of histone deacetylases. This includes protein-protein interactions, changes in the subcellular localization and posttranslational modifications, as well as regulation of their availability either by controlling HDAC expression or proteolytic processing. Mammalian HDACs are classified into three different groups (I, II, and III) according to their sequence homology to yeast HDACs: reduced potassium dependency 3 (Rpd3), histone deacetylase 1 (Hda1), and silent information regulator 2 (Sir2), respectively. In general, HDACs do not make direct contact with DNA and depend on other nucleoproteins for recruitment to specific locations in the genome. HDACs are normally bound to scaffold proteins like Sin3 and are included in large multiprotein complexes (Sin3, NuRD/NRD/Mi2, and the CoREST complexes) that are multifunctional (for a review, see Ref. 280a). The main mechanism that regulates HDAC activity is the protein-protein interaction within the multiprotein complexes. An example of this is the increased enzymatic activity of HDAC3 after the interaction with the silencer complex SMRT/N-CoR (silencing mediator of retinoid and thyroid receptor/nuclear receptor corepressor) (6, 125). The activation mechanism involves the displacement of an inhibitor protein called TCP-1 ring complex (TriC) that is bound to and blocks HDAC3 enzymatic activity (115). Another major mechanism for the regulation of HDAC activity is through phosphorylation. For class I HDACs, phosphorylation by casein kinase II and/or PKA results in increased activity, except for HDAC8, for which it is reduced after PKA phosphorylation (175, 245, 311). In the case of class II HDACs, phosphorylation regulates their subcellular localization and their ability to interact with other proteins. Ca2⫹-dependent phosphorylation of HDAC4 and -5 by CaMKIV thus results in unbinding from MEF-2 proteins and in a multistep Ca2⫹-regulated process that involves the interaction with 14-3-3 proteins, producing important changes in gene expression that result in drastic phenotypic modifications (337, 338). It has been demonstrated that spontaneous electrical activity is sufficient for nuclear export of HDAC4, while stimulation of calcium flux through synaptic NMDA receptors or L-type calcium channels induces the nuclear export of HDAC5. Nuclear import of HDAC4 but not -5 is mediated by sumoylation (158). These differences in the activation thresholds for HDAC4 and HDAC5 nuclear export and the distinct import processes could provide a mechanism for input-specific gene expression (51). Dephosphorylation of HDACs is also a Ca2⫹-sensitive process, since most class I and II HDACs form complexes that include PP1 (44,
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100), although other phosphatases such as PP4 might also participate in the process (343). Finally, activity-dependent regulation of HDAC3 gene expression has been shown in T cells after TCR stimulation by a mechanism that involves repression by HDAC1 at the promoter level (69, 169). Naive T cells are those that have matured in the thymus and emerged into the periphery but have not yet encountered antigen. When these cells are first exposed to antigen, they differentiate into effector T cell with the ability to transcribe specific subsets of cytokine genes in response to secondary stimulation. The process of Th1/ Th2 cell differentiation involves early antigen-induced changes that are transient unless they are maintained by the simultaneous stimulation with the specific cytokines. Induction of Th1 or Th2 lineage-specific differentiation involves the remodeling of the cytokine locus itself in a process that is controlled by NFAT proteins (13, 17) acting on distal regulatory elements present in all cytokine genes that have been examined, including IL-3, granulocyte-macrophage colony stimulating factor, IL-4, IL-10, and IFN-␥ (2, 16, 59, 60, 86, 124). NFAT proteins act together with STAT (signal transducer and activator of transcription) factors to determine the Th1/Th2 lineage. In Th1 cells, STAT1 and STAT4 act downstream of IL-12 and IFN-␥, respectively, while STAT6 acts downstream of IL-4 in Th2 cells. The synergistic action of NFAT and STAT elicits the lineage-specific expression of transcription factors T-bet and GATA3 for Th1 and Th2 differentiation, respectively. At the same time, NFAT cooperates functionally with STAT proteins at cytokine regulatory regions, initiating long-range changes in DNase I hypersensitivity and histone modification throughout the regulatory regions of the IFN-␥ and IL-4 genes (3, 13, 296). The appearance of new DNase I-hypersensitive sites in the IFN-␥ and IL-4 genes during Th1 and Th2 cell differentiation is blocked by CsA, demonstrating the Ca2⫹-dependent involvement of NFAT proteins in the remodeling of cytokine genes (2). Although NFAT proteins bind to the promoters of both IFN-␥ and IL-4 during the early stages of naive T-cell activation, after initiation of Th1 cell differentiation, the locus of IL-4 is silenced resulting in the specific binding of NFAT to the IFN-␥ promoter. Similarly, during Th2 cell differentiation and after silencing of the IFN-␥ locus, NFAT binds to the IL-4 promoter. V. EXEMPLIFYING THE COMPLEXITY OF CALCIUM-DEPENDENT GENE EXPRESSION: THE BRAIN-DERIVED NEUROTROPHIC FACTOR COMPENDIUM The mouse BDNF gene consists of five 5⬘ noncoding exons and one 3⬘ exon that includes the entire ORF of the biologically active protein (305). Each of the first five Physiol Rev • VOL
exons has a 5⬘ flanking region that is transcribed and a splice donor site at the 3⬘ end. Exon VI contains the only splice acceptor site and two polyadenylation signals. By alternative usage of the five promoters followed by splicing with exon VI and alternative usage of the two polyadenylation signals, transcription of the BDNF gene in mice results in 10 different BDNF transcripts. In the rat, the third exon is missing; thus exon III corresponds to mouse exon IV, and so on. Nonetheless, the overall organization and regulation of the promoter regions associated with each exon is basically conserved (305). Early induction of BDNF transcription in the rat brain following neuronal activation occurs through the differential usage of BDNF promoters I and III or IV (99, 213, 305), while in cultured rat cortical neurons, activation of voltage-sensitive calcium channels by increased extracellular K⫹ concentrations results in the preferential upregulation of BDNFIII transcripts (279, 300). Several regulatory sites have been associated with the activitydependent expression of rat BDNF transcripts: binding sites for CREB and USF on promoter I (297), RE-1/NRSE sites recognized by members of the REST/NRSF family on promoter II (306, 344, 345), C/EBP␣ and Sp1 sites that regulate expression from promoter IV (298), and an estrogen-responsive element near exon V (282). In exon III, the initial studies (279, 300) identified two main sites: 1) a hemi-palindromic CRE site that binds CREB and is located between 40 and 30 bp upstream of the exon III mRNA start site, and 2) a Ca2⫹-responsive sequence (CRS-1) located between 72 and 47 bp upstream from the start site. Because the nature of the nuclear factor(s) binding to the CRS-1 site was unknown, activity-dependent regulation of BDNF was initially explained as a kinase-dependent process with Ca2⫹-mediated CaMKIVdependent CREB phosphorylation. Several recent discoveries have modified this simplified notion. Analysis of the rat CRS-1 by Greenberg’s laboratory has identified three independent Ca2⫹-responsive regulatory sites: the CaRE1, CaRE2, and the CaRE3/CRE site located 3⬘ from the CRS-1 site. While the CaRE3/CRE site corresponds to the originally identified calcium responsive element and mediates transactivation of BDNF by the activated CREB/CBP pathway, the other two sites interact with proteins newly characterized as Ca2⫹-responsive regulators of BDNF transcription. The CaRE1 sequence is located at the 5⬘ end of the previously defined CRS-1 site and binds a new protein termed CaRF, calcium responsive factor, identified using a one-hybrid approach in yeast (301). Ability to bind to the CaRE1 sequence resides in the NH2 terminal of CaRF, while the domain(s) responsible for its transactivating properties is located at the COOH terminal. The CaRE2 sequence includes an E-box (CANNTG) that binds to the upstream stimulatory factors 1 and 2 (USF1/2) (52). USF1 and USF2 are ubiquitously expressed bHLH proteins that bind to E-boxes as homo-
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or heterodimers to activate transcription of target genes (272, 281). In addition, work in our laboratory characterized the binding of transcriptional repressor DREAM to two DRE sites located within the CRS-1 sequence (209). This indicates that DREAM may participate directly in the basal as well as in the Ca2⫹-dependent regulation of BDNFIII transcripts. Neither the nuclear translocation of CaRF and USF nor their binding to the CaRE1/CaRE2 sequences, respectively, is affected by changes in the Ca2⫹ concentration. This indicates that the stimulus-dependent transactivating response of CaRF or USF proteins may be mediated by so far unknown posttranscriptional modifications of these factors or by undisclosed CaRF- and USF-interacting proteins that presumably are responsible to sense and to respond to the Ca2⫹ signal (55, 301). Taken together, these results indicate that a CREB-independent, Ca2⫹-dependent regulation of BDNF occurs but may require additional factors. Whether BDNF is a bona fide target gene for CaRF, DREAM, and USF proteins nonetheless remains to be firmly established in vivo using appropriate genetically modified mouse models. Recent studies added a further degree of complexity to the regulation of BDNF expression by showing that DNA methylation and possibly chromatin remodeling control activity-dependent expression of the BDNF gene. Methylation of several CpG islands at the 5⬘ flanking region of BDNF exon III is dramatically reduced following depolarization of primary cultured cortical neurons (202). This finding correlates with the activity-dependent reduction in the binding of methyl-CpG binding protein 2 (MeCP2) to BDNF exon III promoter and the increase in BDNF expression in the brains of DNA methyltransferase I⫺/⫺ (MnmI) and MeCP2⫺/⫺ mice (54, 202). Silencing of BDNF upon MeCP2 binding involves HDAC1 recruitment through the corepressor mSin3A and/or the histone methyltransferase SUV39H1 that dimethylates histone H3 on K9, a hallmark of inactive chromatin structure (94, 202). The mechanism controlling demethylation of CpG islands after K⫹-induced depolarization is presently unknown, although Ca2⫹-dependent phosphorylation of MeCP2 regulates its unbinding from methylated DNA (54). Whether demethylation follows or precedes MeCP2 release from BDNF CpG islands and the signal(s) responsible for resetting basal transcription activity at BDNF promoter III after activity-dependent induction are not known. BDNF is an important neurotrophic factor for neuronal connectivity and brain function (reviewed in Ref. 273a), and heterozygous BDNF deficient mice show important deficits in learning and memory (165). It is therefore not surprising that three devastating neurological disorders have been associated with mutations in proteins that affect or participate in the activity-dependent transactivation of the BDNF gene. These are the Rett syndrome, the Rubinstein-Taybi syndrome, and HuntingPhysiol Rev • VOL
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ton’s disease. In all three cases, a casual relationship with BDNF has been shown in transgenic models that reproduce partial aspects of the disease, although a formal demonstration of modified BDNF levels in the brains of these patients has not yet been provided. The Rett syndrome, an X-linked neurological disorder, is characterized by arrested neurological development and cognitive decline and is produced is most cases by mutations in the MeCP2 protein (10, 276), the methyl CpG binding protein that controls BDNFIII transcription (54, 202). How these mutations relate to changes in BDNF expression in Rett syndrome-derived neurons is not known. The Rubinstein-Taybi syndrome is a rare congenital disorder characterized by severe mental retardation as well as retarded and abnormal skeletal growth. The disease is caused by heterozygous mutations of the CBP gene that affect the COOH-terminal domain of the protein (244). Interventions that increase CREB activity overcome memory deficits in CBP[HAT⫺/⫺] or heterozygous CBP⫺/⫺ mice (5, 166), although changes in BDNF expression in these animal models have not been reported. Huntington’s disease, a dominantly inherited neurodegenerative disorder, is characterized by chorea, cognitive abnormalities, and psychiatric disturbances and is caused by a polyglutamine expansion in the huntingtin protein (reviewed in Ref. 123a). Both gain- and loss-of-
FIG. 7. Multiple molecular mechanisms regulate the activity-dependent transcription of the rat BDNF promoter III. A: “inactive or closed” conformation of the chromatin at the BDNF promoter III as a result of DNA methylation (yellow dots) and the presence of nonacetylated histones (hatched ellipse). B: “active or open” chromatin conformation at the BDNF promoter III region showing the different regulatory sites and the nucleoproteins that interact with them. For details, see section V in the text.
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function of the mutated protein have been associated with mechanisms that affect BDNF expression. The gain-offunction mechanism involves the interaction of mutated huntingtin with CBP and other nucleoproteins such as p53 and TBP that impairs cAMP-dependent transcription (150, 273, 286, 292). The loss-of-function mechanism relates to the ability of wild-type huntingtin, absent in the polyglutamine extended mutated version, to interact with the neuron-specific repressor REST/NRSF, preventing its nuclear localization and repressive effect on the transcription of the BDNF promoter II (344, 345). A summary of the mechanisms operating on the expression of BDNF exon III is shown in Figure 7. Further studies are needed to understand the global and exonspecific mechanisms by which Ca2⫹regulates BDNF gene expression in different neuronal populations. It will be particularly important to assess whether the multiple mechanisms regulating activity-dependent regulation of BDNF promoter III operate at the same time in a given neuron, and the Ca2⫹ level requirements that are needed to activate each of these mechanisms and hence the type of stimulus that will successfully trigger one specific pathway.
nuclear pool as well as mechanisms that control the passage of calcium ions through the nuclear pore should also be provided. Whether the nuclear pools of phosphoinositides and calcium maintain a certain level of cross-talk to affect chromatin remodeling and to influence transcriptional networks more directly are open questions looking for an answer. ACKNOWLEDGMENTS
We thank Dr. Lafarga and Dr. Berciano for immunocytochemistry in sensory neurons and C. Marks for critical reading of the manuscript. We apologize to those authors whose work we could not include due to space limitations. Address for reprint requests and other correspondence: J. R. Naranjo, CNB, CSIC Campus de Cantoblanco, 28049 Madrid, Spain (e-mail:
[email protected]). GRANTS
B. Mellstro¨m is supported by a Ramon y Cajal Senior Scientist Contract. M. Savignac and R. Gomez-Villafuertes are supported by CEE-Marie Curie and J. De la Cierva Junior Scientist Contracts, respectively. The work in our laboratory is supported by grants from the Human Frontiers Science Program (RGP0156/2001), CEE (NoE/512032), Fundacion La Caixa, MEC, FISS, and CAM.
VI. SUMMARY AND FUTURE DIRECTIONS In addition to the well-known calcium-activated kinase- and phosphatase-dependent mechanisms that control gene expression, recent years have witnessed an eruption of new calcium-sensitive proteins and calciumdependent pathways. This has added further complexity to, and raised new questions about, the mechanisms that impose spatial and temporal restrictions on the synchronically induced transcriptional activity at a given genomic locus to control its expression profile. Also, it will be very important to define the hierarchy of calcium-operated pathways that simultaneously operate on the expression of a given gene. New experimental work has provided insights into the nature and specificities of the calcium signal itself, although it is still unclear how the different pools of free intracellular calcium differentially activate or repress a given transcriptional network. Many still unknown selfregulatory mechanisms probably participate in the finetuning of the transcriptional response in absolute terms, as well as of the temporal characteristics of the response. Finally, recent publications highlight the existence of a nuclear pool of phosphoinositides and the emerging role of nuclear inositol phosphates in gene expression (228, 277, 287). New evidence has argued in favor of a similarly regulated nuclear calcium pool (88), although further studies should establish indisputably that such a pool is truly nuclear and independent from the ER pool. Mechanisms that might regulate the release of Ca2⫹ from such a Physiol Rev • VOL
REFERENCES 1. Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S. PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75: 1263–1271, 1993. 2. Agarwal S, Avni O, Rao A. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity 12: 643– 652, 2000. 3. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9: 765–775, 1998. 4. Aizawa H, Hu SC, Bobb K, Balakrishnan K, Ince G, Gurevich I, Cowan M, Ghosh A. Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303: 197–202, 2004. 5. Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A. Chromatin acetylation, memory, and LTP are impaired in CBP⫹/⫺ mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42: 947– 959, 2004. 6. Alland L, Muhle R, Hou H Jr, Potes J, Chin L, Schreiber-Agus N, DePinho RA. Role for N-CoR and histone deacetylase in Sin3mediated transcriptional repression. Nature 387: 49 –55, 1997. 7. Allen PB, Hvalby O, Jensen V, Errington ML, Ramsay M, Chaudhry FA, Bliss TV, Storm-Mathisen J, Morris RG, Andersen P, Greengard P. Protein phosphatase-1 regulation in the induction of long-term potentiation: heterogeneous molecular mechanisms. J Neurosci 20: 3537–3543, 2000. 8. Allen PB, Kwon YG, Nairn AC, Greengard P. Isolation and characterization of PNUTS, a putative protein phosphatase 1 nuclear targeting subunit. J Biol Chem 273: 4089 – 4095, 1998. 9. Ambudkar IS, Ong HL, Liu X, Bandyopadhyay B, Cheng KT. TRPC1: the link between functionally distinct store-operated calcium channels. Cell Calcium 42: 213–223, 2007. 10. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23: 185–188, 1999.
88 • APRIL 2008 •
www.prv.org
Ca2⫹-REGULATED GENE EXPRESSION 11. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ. Modulation of A-type potassium channels by a family of calcium sensors. Nature 403: 553–556, 2000. 12. Anderson KA, Means AR. Defective signaling in a subpopulation of CD4(⫹) T cells in the absence of Ca(2⫹)/calmodulin-dependent protein kinase IV. Mol Cell Biol 22: 23–29, 2002. 13. Ansel KM, Lee DU, Rao A. An epigenetic view of helper T cell differentiation. Nat Immunol 4: 616 – 623, 2003. 14. Argentaro A, Sim H, Kelly S, Preiss S, Clayton A, Jans DA, Harley VR. A SOX9 defect of calmodulin-dependent nuclear import in campomelic dysplasia/autosomal sex reversal. J Biol Chem 278: 33839 –33847, 2003. 15. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441: 595– 600, 2006. 16. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 3: 643– 651, 2002. 17. Avni O, Rao A. T cell differentiation: a mechanistic view. Curr Opin Immunol 12: 654 – 659, 2000. 18. Baksh S, Widlund HR, Frazer-Abel AA, Du J, Fosmire S, Fisher DE, DeCaprio JA, Modiano JF, Burakoff SJ. NFATc2mediated repression of cyclin-dependent kinase 4 expression. Mol Cell 10: 1071–1081, 2002. 19. Bandyopadhyay J, Lee J, Bandyopadhyay A. Regulation of calcineurin, a calcium/calmodulin-dependent protein phosphatase, in C. elegans. Mol Cells 18: 10 –16, 2004. 20. Banks GC, Li Y, Reeves R. Differential in vivo modifications of the HMGI(Y) nonhistone chromatin proteins modulate nucleosome and DNA interactions. Biochemistry 39: 8333– 8346, 2000. 21. Barford D, Das AK, Egloff MP. The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annu Rev Biophys Biomol Struct 27: 133–164, 1998. 22. Baudier J, Bergeret E, Bertacchi N, Weintraub H, Gagnon J, Garin J. Interactions of myogenic bHLH transcription factors with calcium-binding calmodulin and S100a (alpha alpha) proteins. Biochemistry 34: 7834 –7846, 1995. 23. Bayer KU, De Koninck P, Leonard AS, Hell JW, Schulman H. Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411: 801– 805, 2001. 24. Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275: 1930 –1934, 1997. 25. Beg AA, Ruben SM, Scheinman RI, Haskill S, Rosen CA, Baldwin AS Jr. I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention. Genes Dev 6: 1899 –1913, 1992. 26. Belfield JL, Whittaker C, Cader MZ, Chawla S. Differential effects of Ca2⫹ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons. J Biol Chem 281: 27724 –27732, 2006. 27. Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1: 11–21, 2000. 28. Beullens M, Van Eynde A, Bollen M, Stalmans W. Inactivation of nuclear inhibitory polypeptides of protein phosphatase-1 (NIPP-1) by protein kinase A. J Biol Chem 268: 13172–13177, 1993. 29. Bito H, Deisseroth K, Tsien RW. CREB phosphorylation and dephosphorylation: a Ca(2⫹)- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87: 1203–1214, 1996. 30. Bittinger MA, McWhinnie E, Meltzer J, Iourgenko V, Latario B, Liu X, Chen CH, Song C, Garza D, Labow M. Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins. Curr Biol 14: 2156 –2161, 2004. 31. Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol 14: 167–196, 1998. 32. Blaeser F, Ho N, Prywes R, Chatila TA. Ca(2⫹)-dependent gene expression mediated by MEF2 transcription factors. J Biol Chem 275: 197–209, 2000. Physiol Rev • VOL
441
33. Blitzer RD, Connor JH, Brown GP, Wong T, Shenolikar S, Iyengar R, Landau EM. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280: 1940 –1942, 1998. 34. Bourtchouladze R, Lidge R, Catapano R, Stanley J, Gossweiler S, Romashko D, Scott R, Tully T. A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc Natl Acad Sci USA 100: 10518 –10522, 2003. 35. Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med 10: 248 –254, 2004. 36. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267: 1485–1488, 1995. 37. Bueno OF, Brandt EB, Rothenberg ME, Molkentin JD. Defective T cell development and function in calcineurin A beta-deficient mice. Proc Natl Acad Sci USA 99: 9398 –9403, 2002. 38. Bueno OF, Wilkins BJ, Tymitz KM, Glascock BJ, Kimball TF, Lorenz JN, Molkentin JD. Impaired cardiac hypertrophic response in Calcineurin Abeta-deficient mice. Proc Natl Acad Sci USA 99: 4586 – 4591, 2002. 39. Bui JD, Calbo S, Hayden-Martinez K, Kane LP, Gardner P, Hedrick SM. A role for CaMKII in T cell memory. Cell 100: 457– 467, 2000. 40. Burns K, Duggan B, Atkinson EA, Famulski KS, Nemer M, Bleackley RC, Michalak M. Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. Nature 367: 476 – 480, 1994. 41. Butcher GQ, Lee B, Cheng HY, Obrietan K. Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/ MAP kinase-dependent mechanism. J Neurosci 25: 5305–5313, 2005. 42. Buxbaum JD, Choi EK, Luo Y, Lilliehook C, Crowley AC, Merriam DE, Wasco W. Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nat Med 4: 1177–1181, 1998. 43. Cameron AM, Steiner JP, Roskams AJ, Ali SM, Ronnett GV, Snyder SH. Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2⫹ flux. Cell 83: 463– 472, 1995. 44. Canettieri G, Morantte I, Guzman E, Asahara H, Herzig S, Anderson SD, Yates JR 3rd, Montminy M. Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex. Nat Struct Biol 10: 175–181, 2003. 45. Carafoli E. Calcium signaling: a tale for all seasons. Proc Natl Acad Sci USA 99: 1115–1122, 2002. 46. Carrion AM, Link WA, Ledo F, Mellstrom B, Naranjo JR. DREAM is a Ca2⫹-regulated transcriptional repressor. Nature 398: 80 – 84, 1999. 47. Carrion AM, Mellstrom B, Naranjo JR. Protein kinase A-dependent derepression of the human prodynorphin gene via differential binding to an intragenic silencer element. Mol Cell Biol 18: 6921– 6929, 1998. 48. Cha-Molstad H, Keller DM, Yochum GS, Impey S, Goodman RH. Cell-type-specific binding of the transcription factor CREB to the cAMP-response element. Proc Natl Acad Sci USA 101: 13572– 13577, 2004. 49. Chadee DN, Hendzel MJ, Tylipski CP, Allis CD, Bazett-Jones DP, Wright JA, Davie JR. Increased Ser-10 phosphorylation of histone H3 in mitogen-stimulated and oncogene-transformed mouse fibroblasts. J Biol Chem 274: 24914 –24920, 1999. 50. Chau KY, Munshi N, Keane-Myers A, Cheung-Chau KW, Tai AK, Manfioletti G, Dorey CK, Thanos D, Zack DJ, Ono SJ. The architectural transcription factor high mobility group I(Y) participates in photoreceptor-specific gene expression. J Neurosci 20: 7317–7324, 2000. 51. Chawla S, Vanhoutte P, Arnold FJ, Huang CL, Bading H. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J Neurochem 85: 151–159, 2003.
88 • APRIL 2008 •
www.prv.org
442
MELLSTRO¨M ET AL.
52. Chen C, Rainnie DG, Greene RW, Tonegawa S. Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II. Science 266: 291–294, 1994. 53. Chen SR, Zhang L, MacLennan DH. Asymmetrical blockade of the Ca2⫹ release channel (ryanodine receptor) by 12-kDa FK506 binding protein. Proc Natl Acad Sci USA 91: 11953–11957, 1994. 54. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302: 885– 889, 2003. 55. Chen WG, West AE, Tao X, Corfas G, Szentirmay MN, Sawadogo M, Vinson C, Greenberg ME. Upstream stimulatory factors are mediators of Ca2⫹-responsive transcription in neurons. J Neurosci 23: 2572–2581, 2003. 56. Cheng HY, Laviolette SR, van der Kooy D, Penninger JM. DREAM ablation selectively alters THC place aversion and analgesia but leaves intact the motivational and analgesic effects of morphine. Eur J Neurosci 19: 3033–3041, 2004. 57. Chow CW, Rincon M, Cavanagh J, Dickens M, Davis RJ. Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science 278: 1638 –1641, 1997. 58. Clayton AL, Rose S, Barratt MJ, Mahadevan LC. Phosphoacetylation of histone H3 on c-fos- and c-jun-associated nucleosomes upon gene activation. EMBO J 19: 3714 –3726, 2000. 59. Cockerill PN, Bert AG, Jenkins F, Ryan GR, Shannon MF, Vadas MA. Human granulocyte-macrophage colony-stimulating factor enhancer function is associated with cooperative interactions between AP-1 and NFATp/c. Mol Cell Biol 15: 2071–2079, 1995. 60. Cockerill PN, Shannon MF, Bert AG, Ryan GR, Vadas MA. The granulocyte-macrophage colony-stimulating factor/interleukin 3 locus is regulated by an inducible cyclosporin A-sensitive enhancer. Proc Natl Acad Sci USA 90: 2466 –2470, 1993. 61. Conkright MD, Guzman E, Flechner L, Su AI, Hogenesch JB, Montminy M. Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. Mol Cell 11: 1101–1108, 2003. 62. Corcoran EE, Means AR. Defining Ca2⫹/calmodulin-dependent protein kinase cascades in transcriptional regulation. J Biol Chem 276: 2975–2978, 2001. 63. Corneliussen B, Holm M, Waltersson Y, Onions J, Hallberg B, Thornell A, Grundstrom T. Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains. Nature 368: 760 –764, 1994. 64. Crabtree GR. Generic signals and specific outcomes: signaling through Ca2⫹, calcineurin, NF-AT. Cell 96: 611– 614, 1999. 65. Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell Suppl 109: S67–S79, 2002. 66. Craig TA, Benson LM, Venyaminov SY, Klimtchuk ES, Bajzer Z, Prendergast FG, Naylor S, Kumar R. The metal-binding properties of DREAM: evidence for calcium-mediated changes in DREAM structure. J Biol Chem 277: 10955–10966, 2002. 67. Crosio C, Cermakian N, Allis CD, Sassone-Corsi P. Light induces chromatin modification in cells of the mammalian circadian clock. Nat Neurosci 3: 1241–1247, 2000. 68. Cyert MS. Calcineurin signaling in Saccharomyces cerevisiae: how yeast go crazy in response to stress. Biochem Biophys Res Commun 311: 1143–1150, 2003. 69. Dangond F, Hafler DA, Tong JK, Randall J, Kojima R, Utku N, Gullans SR. Differential display cloning of a novel human histone deacetylase (HDAC3) cDNA from PHA-activated immune cells. Biochem Biophys Res Commun 242: 648 – 652, 1998. 70. Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, Carinci P, Min KT, Fox DS, Cunningham KW, Bassel-Duby R, Olson EN, Zhang Z, Williams RS, Gerber HP, Perez-Riba M, Seo H, Cao X, Klee CB, Redondo JM, Maltais LJ, Bruford EA, Povey S, Molkentin JD, McKeon FD, Duh EJ, Crabtree GR, Cyert MS, de la Luna S, Estivill X. Renaming the DSCR1/ Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J 21: 3023–3028, 2000. 71. De la Pompa JL, Timmerman LA, Takimoto H, Yoshida H, Elia AJ, Samper E, Potter J, Wakeham A, Marengere L, Langille Physiol Rev • VOL
72.
73.
74.
75. 76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
BL, Crabtree GR, Mak TW. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392: 182–186, 1998. De Windt LJ, Lim HW, Bueno OF, Liang Q, Delling U, Braz JC, Glascock BJ, Kimball TF, del Monte F, Hajjar RJ, Molkentin JD. Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 98: 3322–3327, 2001. Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, may mediate activation of CREB. EMBO J 17: 4426 – 4441, 1998. Dedhar S, Rennie PS, Shago M, Hagesteijn CY, Yang H, Filmus J, Hawley RG, Bruchovsky N, Cheng H, Matusik RJ, Giguère V. Inhibition of nuclear hormone receptor activity by calreticulin. Nature 367: 480 – 483, 1994. DeFranco DB. Nuclear export: DNA-binding domains find a surprising partner. Curr Biol 11: R1036 –1037, 2001. Deisseroth K, Mermelstein PG, Xia H, Tsien RW. Signaling from synapse to nucleus: the logic behind the mechanisms. Curr Opin Neurobiol 13: 354 –365, 2003. Deisseroth K, Tsien RW. Dynamic multiphosphorylation passwords for activity-dependent gene expression. Neuron 34: 179 –182, 2002. Deucher A, Efimova T, Eckert RL. Calcium-dependent involucrin expression is inversely regulated by protein kinase C (PKC)alpha and PKCdelta. J Biol Chem 277: 17032–17040, 2002. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388: 548 –554, 1997. Ding HF, Rimsky S, Batson SC, Bustin M, Hansen U. Stimulation of RNA polymerase II elongation by chromosomal protein HMG-14. Science 265: 796 –799, 1994. Divecha N, Rhee SG, Letcher AJ, Irvine RF. Phosphoinositide signalling enzymes in rat liver nuclei: phosphoinositidase C isoform beta 1 is specifically, but not predominantly, located in the nucleus. Biochem J 289: 617– 620, 1993. Dlugosz AA, Yuspa SH. Coordinate changes in gene expression which mark the spinous to granular cell transition in epidermis are regulated by protein kinase C. J Cell Biol 120: 217–225, 1993. Dobi A, von Agoston D. Submillimolar levels of calcium regulates DNA structure at the dinucleotide repeat (TG/AC)n. Proc Natl Acad Sci USA 95: 5981–5986, 1998. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of transcription factors induced by Ca2⫹ response amplitude and duration. Nature 386: 855– 858, 1997. Dolmetsch RE, Xu K, Lewis RS. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392: 933–936, 1998. Duncliffe KN, Bert AG, Vadas MA, Cockerill PN. A T cellspecific enhancer in the interleukin-3 locus is activated cooperatively by Oct and NFAT elements within a DNase I-hypersensitive site. Immunity 6: 175–185, 1997. Dzialo-Hatton R, Milbrandt J, Hockett RD Jr, Weaver CT. Differential expression of Fas ligand in Th1 and Th2 cells is regulated by early growth response gene and NF-AT family members. J Immunol 166: 4534 – 4542, 2001. Echevarria W, Leite MF, Guerra MT, Zipfel WR, Nathanson MH. Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nat Cell Biol 5: 440 – 446, 2003. El-Armouche A, Bednorz A, Pamminger T, Ditz D, Didie M, Dobrev D, Eschenhagen T. Role of calcineurin and protein phosphatase-2A in the regulation of phosphatase inhibitor-1 in cardiac myocytes. Biochem Biophys Res Commun 346: 700 –706, 2006. Ermak G, Harris CD, Davies KJ. The DSCR1 (Adapt78) isoform 1 protein calcipressin 1 inhibits calcineurin and protects against acute calcium-mediated stress damage, including transient oxidative stress. FASEB J 16: 814 – 824, 2002. Feng JL, Villeponteau B. Serum stimulation of the c-fos enhancer induces reversible changes in c-fos chromatin structure. Mol Cell Biol 10: 1126 –1133, 1990. Feng JM, Hu YK, Xie LH, Colwell CS, Shao XM, Sun XP, Chen B, Tang H, Campagnoni AT. Golli protein negatively regulates
88 • APRIL 2008 •
www.prv.org
Ca2⫹-REGULATED GENE EXPRESSION
93.
94.
95.
96.
97.
98.
99.
100.
101. 102.
103.
104.
105.
106.
107.
108. 109.
110.
111.
112.
store depletion-induced calcium influx in T cells. Immunity 24: 717–727, 2006. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441: 179 –185, 2006. Fischle W, Wang Y, Allis CD. Binary switches and modification cassettes in histone biology and beyond. Nature 425: 475– 479, 2003. Frey N, Barrientos T, Shelton JM, Frank D, Rutten H, Gehring D, Kuhn C, Lutz M, Rothermel B, Bassel-Duby R, Richardson JA, Katus HA, Hill JA, Olson EN. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nat Med 10: 1336 –1343, 2004. Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci USA 97: 14632–14637, 2000. Fricker M, Hollinshead M, White N, Vaux D. Interphase nuclei of many mammalian cell types contain deep, dynamic, tubular membrane-bound invaginations of the nuclear envelope. J Cell Biol 136: 531–544, 1997. Fuentes JJ, Genesca L, Kingsbury TJ, Cunningham KW, Perez-Riba M, Estivill X, de la Luna S. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 9: 1681–1690, 2000. Funakoshi H, Frisen J, Barbany G, Timmusk T, Zachrisson O, Verge VM, Persson H. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol 123: 455– 465, 1993. Galasinski SC, Resing KA, Goodrich JA, Ahn NG. Phosphatase inhibition leads to histone deacetylases 1 and 2 phosphorylation and disruption of corepressor interactions. J Biol Chem 277: 19618 –19626, 2002. Gallo EM, Cante-Barrett K, Crabtree GR. Lymphocyte calcium signaling from membrane to nucleus. Nat Immunol 7: 25–32, 2006. Genoux D, Haditsch U, Knobloch M, Michalon A, Storm D, Mansuy IM. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418: 970 –975, 2002. Gerasimenko OV, Gerasimenko JV, Tepikin AV, Petersen OH. ATP-dependent accumulation and inositol trisphosphate- or cyclic ADP-ribose-mediated release of Ca2⫹ from the nuclear envelope. Cell 80: 439 – 444, 1995. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16: 225–260, 1998. Gomez M, De Castro E, Guarin E, Sasakura H, Kuhara A, Mori I, Bartfai T, Bargmann CI, Nef P. Ca2⫹ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans. Neuron 30: 241–248, 2001. Gomez-Ospina N, Tsuruta F, Barreto-Chang O, Hu L, Dolmetsch R. The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell 127: 591– 606, 2006. Gomez-Villafuertes R, Torres B, Barrio J, Savignac M, Gabellini N, Rizzato F, Pintado B, Gutierrez-Adan A, Mellstrom B, Carafoli E, Naranjo JR. Downstream regulatory element antagonist modulator regulates Ca2⫹ homeostasis and viability in cerebellar neurons. J Neurosci 25: 10822–10830, 2005. Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, development. Genes Dev 14: 1553–1577, 2000. Gordon JA, Cioffi D, Silva AJ, Stryker MP. Deficient plasticity in the primary visual cortex of alpha-calcium/calmodulin-dependent protein kinase II mutant mice. Neuron 17: 491– 499, 1996. Graef IA, Chen F, Chen L, Kuo A, Crabtree GR. Signals transduced by Ca(2⫹)/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 105: 863– 875, 2001. Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401: 703–708, 1999. Graef IA, Wang F, Charron F, Chen L, Neilson J, TessierLavigne M, Crabtree GR. Neurotrophins and netrins require calPhysiol Rev • VOL
443
cineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113: 657– 670, 2003. 113. Griffith LC. Regulation of calcium/calmodulin-dependent protein kinase II activation by intramolecular and intermolecular interactions. J Neurosci 24: 8394 – 8398, 2004. 114. Griffith LC, Lu CS, Sun XX. CaMKII, an enzyme on the move: regulation of temporospatial localization. Mol Interv 3: 386 – 403, 2003. 115. Guenther MG, Yu J, Kao GD, Yen TJ, Lazar MA. Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex. Genes Dev 16: 3130 –3135, 2002. 116. Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A. A genomewide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441: 646 – 650, 2006. 117. Haberland M, Arnold MA, McAnally J, Phan D, Kim Y, Olson EN. Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation. Mol Cell Biol 27: 518 –525, 2007. 118. Hagar RE, Burgstahler AD, Nathanson MH, Ehrlich BE. Type III InsP3 receptor channel stays open in the presence of increased calcium. Nature 396: 81– 84, 1998. 119. Hagiwara M, Alberts A, Brindle P, Meinkoth J, Feramisco J, Deng T, Karin M, Shenolikar S, Montminy M. Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB. Cell 70: 105–113, 1992. 120. Hardingham GE, Chawla S, Cruzalegui FH, Bading H. Control of recruitment and transcription-activating function of CBP determines gene regulation by NMDA receptors and L-type calcium channels. Neuron 22: 789 –798, 1999. 121. Hardingham GE, Chawla S, Johnson CM, Bading H. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385: 260 –265, 1997. 122. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5: 405– 414, 2002. 123. Harhaj EW, Sun SC. IkappaB kinases serve as a target of CD28 signaling. J Biol Chem 273: 25185–25190, 1998. 123a.Harper PS. New genes for old diseases: the molecular basis of myotonic dystrophy and Huntington’s disease. The Lumleian Lecture 1995. J R Coll Physicians Lond 30: 221–231, 1996. 124. Hawwari A, Burrows J, Vadas MA, Cockerill PN. The human IL-3 locus is regulated cooperatively by two NFAT-dependent enhancers that have distinct tissue-specific activities. J Immunol 169: 1876 –1886, 2002. 125. Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387: 43– 48, 1997. 126. Hell JW, Westenbroek RE, Warner C, Ahlijanian MK, Prystay W, Gilbert MM, Snutch TP, Catterall WA. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits. J Cell Biol 123: 949 –962, 1993. 127. Hilioti Z, Gallagher DA, Low-Nam ST, Ramaswamy P, Gajer P, Kingsbury TJ, Birchwood CJ, Levchenko A, Cunningham KW. GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Genes Dev 18: 35– 47, 2004. 128. Hill JA. Electrical remodeling in cardiac hypertrophy. Trends Cardiovasc Med 13: 316 –322, 2003. 129. Ho N, Liauw JA, Blaeser F, Wei F, Hanissian S, Muglia LM, Wozniak DF, Nardi A, Arvin KL, Holtzman DM, Linden DJ, Zhuo M, Muglia LJ, Chatila TA. Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2⫹/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J Neurosci 20: 6459 – 6472, 2000. 129a.Hoeflich KP, Ikura M. Calmodulin in action: diversity in target recognition and activation mechanisms. Cell 108: 739 –742, 2002. 130. Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, NFAT. Genes Dev 17: 2205–2232, 2003.
88 • APRIL 2008 •
www.prv.org
444
MELLSTRO¨M ET AL.
131. Holaska JM, Black BE, Love DC, Hanover JA, Leszyk J, Paschal BM. Calreticulin is a receptor for nuclear export. J Cell Biol 152: 127–140, 2001. 132. Holaska JM, Black BE, Rastinejad F, Paschal BM. Ca2⫹-dependent nuclear export mediated by calreticulin. Mol Cell Biol 22: 6286 – 6297, 2002. 133. Hong CS, Saint-Jeannet JP. Sox proteins and neural crest development. Semin Cell Dev Biol 16: 694 –703, 2005. 134. Hook SS, Means AR. Ca(2⫹)/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol 41: 471–505, 2001. 135. Hu SC, Chrivia J, Ghosh A. Regulation of CBP-mediated transcription by neuronal calcium signaling. Neuron 22: 799 – 808, 1999. 136. Hu X, Lazar MA. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402: 93–96, 1999. 137. Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF. STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol 8: 1003–1010, 2006. 138. Hubbard MJ, Cohen P. On target with a new mechanism for the regulation of protein phosphorylation. Trends Biochem Sci 18: 172–177, 1993. 139. Hudmon A, Schulman H. Neuronal Ca2⫹/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Annu Rev Biochem 71: 473–510, 2002. 140. Hudmon A, Schulman H. Structure-function of the multifunctional Ca2⫹/calmodulin-dependent protein kinase II. Biochem J 364: 593– 611, 2002. 141. Hughes K, Edin S, Antonsson A, Grundstrom T. Calmodulindependent kinase II mediates T cell receptor/CD3- and phorbol ester-induced activation of IkappaB kinase. J Biol Chem 276: 36008 –36013, 2001. 142. Hulme JT, Yarov-Yarovoy V, Lin TW, Scheuer T, Catterall WA. Autoinhibitory control of the CaV1.2 channel by its proteolytically processed distal C-terminal domain. J Physiol 576: 87–102, 2006. 143. Impey S, Fong AL, Wang Y, Cardinaux JR, Fass DM, Obrietan K, Wayman GA, Storm DR, Soderling TR, Goodman RH. Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV. Neuron 34: 235–244, 2002. 144. Ince-Dunn G, Hall BJ, Hu SC, Ripley B, Huganir RL, Olson JM, Tapscott SJ, Ghosh A. Regulation of thalamocortical patterning and synaptic maturation by NeuroD2. Neuron 49: 683– 695, 2006. 145. Iourgenko V, Zhang W, Mickanin C, Daly I, Jiang C, Hexham JM, Orth AP, Miraglia L, Meltzer J, Garza D, Chirn GW, McWhinnie E, Cohen D, Skelton J, Terry R, Yu Y, Bodian D, Buxton FP, Zhu J, Song C, Labow MA. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc Natl Acad Sci USA 100: 12147–12152, 2003. 146. Irvine RF. “Quantal” Ca2⫹ release and the control of Ca2⫹ entry by inositol phosphates—a possible mechanism. FEBS Lett 263: 5–9, 1990. 147. Israel A. The IKK complex: an integrator of all signals that activate NF-kappaB? Trends Cell Biol 10: 129 –133, 2000. 148. Jacobs EC, Pribyl TM, Feng JM, Kampf K, Spreur V, Campagnoni C, Colwell CS, Reyes SD, Martin M, Handley V, Hiltner TD, Readhead C, Jacobs RE, Messing A, Fisher RS, Campagnoni AT. Region-specific myelin pathology in mice lacking the golli products of the myelin basic protein gene. J Neurosci 25: 7004 – 7013, 2005. 149. Jang H, Choi DE, Kim H, Cho EJ, Youn HD. Cabin1 represses MEF2 transcriptional activity by association with a methyltransferase, SUV39H1. J Biol Chem 282: 11172–11179, 2006. 150. Jiang H, Nucifora FC Jr, Ross CA, DeFranco DB. Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein. Hum Mol Genet 12: 1–12, 2003. 151. Johnson EN, Lee YM, Sander TL, Rabkin E, Schoen FJ, Kaushal S, Bischoff J. NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. J Biol Chem 278: 1686 –1692, 2003. 152. Kano M, Hashimoto K, Chen C, Abeliovich A, Aiba A, Kurihara H, Watanabe M, Inoue Y, Tonegawa S. Impaired synapse Physiol Rev • VOL
153.
154.
155.
156.
157. 158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
elimination during cerebellar development in PKC gamma mutant mice. Cell 83: 1223–1231, 1995. Kardalinou E, Zhelev N, Hazzalin CA, Mahadevan LC. Anisomycin and rapamycin define an area upstream of p70/85S6k containing a bifurcation to histone H3-HMG-like protein phosphorylation and c-fos-c-jun induction. Mol Cell Biol 14: 1066 –1074, 1994. Kawabata H, Kawahara K, Kanekura T, Araya N, Daitoku H, Hatta M, Miura N, Fukamizu A, Kanzaki T, Maruyama I, Nakajima T. Possible role of transcriptional coactivator P/CAF and nuclear acetylation in calcium-induced keratinocyte differentiation. J Biol Chem 277: 8099 – 8105, 2002. Kidd JF, Pilkington MF, Schell MJ, Fogarty KE, Skepper JN, Taylor CW, Thorn P. Paclitaxel affects cytosolic calcium signals by opening the mitochondrial permeability transition pore. J Biol Chem 277: 6504 – 6510, 2002. Kim YM, Watanabe T, Allen PB, Kim YM, Lee SJ, Greengard P, Nairn AC, Kwon YG. PNUTS, a protein phosphatase 1 (PP1) nuclear targeting subunit. Characterization of its PP1- and RNAbinding domains and regulation by phosphorylation. J Biol Chem 278: 13819 –13828, 2003. Kingsbury TJ, Cunningham KW. A conserved family of calcineurin regulators. Genes Dev 14: 1595–1604, 2000. Kirsh O, Seeler JS, Pichler A, Gast A, Muller S, Miska E, Mathieu M, Harel-Bellan A, Kouzarides T, Melchior F, Dejean A. The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J 21: 2682–2691, 2002. Kiselyov K, Xu X, Mozhayeva G, Kuo T, Pessah I, Mignery G, Zhu X, Birnbaumer L, Muallem S. Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature 396: 478 – 482, 1998. Klauck TM, Faux MC, Labudda K, Langeberg LK, Jaken S, Scott JD. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271: 1589 –1592, 1996. Koizumi S, Lipp P, Berridge MJ, Bootman MD. Regulation of ryanodine receptor opening by lumenal Ca(2⫹) underlies quantal Ca(2⫹) release in PC12 cells. J Biol Chem 274: 33327–33333, 1999. Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, Takemori H, Montminy M. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437: 1109 –1111, 2005. Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. C-termini of P/Q-type Ca2⫹ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet 15: 1587–1599, 2006. Kornhauser JM, Cowan CW, Shaywitz AJ, Dolmetsch RE, Griffith EC, Hu LS, Haddad C, Xia Z, Greenberg ME. CREB transcriptional activity in neurons is regulated by multiple, calciumspecific phosphorylation events. Neuron 34: 221–233, 2002. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA 92: 8856 – 8860, 1995. Korzus E, Rosenfeld MG, Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42: 961–972, 2004. Kubodera T, Yokota T, Ohwada K, Ishikawa K, Miura H, Matsuoka T, Mizusawa H. Proteolytic cleavage and cellular toxicity of the human alpha1A calcium channel in spinocerebellar ataxia type 6. Neurosci Lett 341: 74 –78, 2003. Kuhara A, Inada H, Katsura I, Mori I. Negative regulation and gain control of sensory neurons by the C. elegans calcineurin TAX-6. Neuron 33: 751–763, 2002. Lagger G, O’Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T, Seiser C. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 21: 2672–2681, 2002. Lai MM, Burnett PE, Wolosker H, Blackshaw S, Snyder SH. Cain, a novel physiologic protein inhibitor of calcineurin. J Biol Chem 273: 18325–18331, 1998. Landsverk HB, Kirkhus M, Bollen M, Kuntziger T, Collas P. PNUTS enhances in vitro chromosome decondensation in a PP1dependent manner. Biochem J 390: 709 –717, 2005.
88 • APRIL 2008 •
www.prv.org
Ca2⫹-REGULATED GENE EXPRESSION 172. Le Douarin B, Nielsen AL, Garnier JM, Ichinose H, Jeanmougin F, Losson R, Chambon P. A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors. EMBO J 15: 6701– 6715, 1996. 173. Ledo F, Carrion AM, Link WA, Mellstrom B, Naranjo JR. DREAM-alphaCREM interaction via leucine-charged domains derepresses downstream regulatory element-dependent transcription. Mol Cell Biol 20: 9120 –9126, 2000. 174. Ledo F, Kremer L, Mellstrom B, Naranjo JR. Ca2⫹-dependent block of CREB-CBP transcription by repressor DREAM. EMBO J 21: 4583– 4592, 2002. 175. Lee H, Rezai-Zadeh N, Seto E. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Mol Cell Biol 24: 765–773, 2004. 176. Lee MG, Zeng W, Muallem S. Characterization and localization of P2 receptors in rat submandibular gland acinar and duct cells. J Biol Chem 272: 32951–32955, 1997. 177. Lenormand JL, Benayoun B, Guillier M, Vandromme M, Leibovitch MP, Leibovitch SA. Mos activates myogenic differentiation by promoting heterodimerization of MyoD and E12 proteins. Mol Cell Biol 17: 584 –593, 1997. 178. Lesage B, Beullens M, Nuytten M, Van Eynde A, Keppens S, Himpens B, Bollen M. Interactor-mediated nuclear translocation and retention of protein phosphatase-1. J Biol Chem 279: 55978 – 55984, 2004. 179. Lewis RS. Calcium signaling mechanisms in T lymphocytes. Annu Rev Immunol 19: 497–521, 2001. 180. Lewis RS. The molecular choreography of a store-operated calcium channel. Nature 446: 284 –287, 2007. 181. Li W, Llopis J, Whitney M, Zlokarnik G, Tsien RY. Cell-permeant caged InsP3 ester shows that Ca2⫹ spike frequency can optimize gene expression. Nature 392: 936 –941, 1998. 182. Lin Q, Schwarz J, Bucana C, Olson EN. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276: 1404 –1407, 1997. 183. Lin X, O’Mahony A, Mu Y, Geleziunas R, Greene WC. Protein kinase C-theta participates in NF-kappaB activation induced by CD3-CD28 costimulation through selective activation of IkappaB kinase beta. Mol Cell Biol 20: 2933–2940, 2000. 184. Lin X, Sikkink RA, Rusnak F, Barber DL. Inhibition of calcineurin phosphatase activity by a calcineurin B homologous protein. J Biol Chem 274: 36125–36131, 1999. 185. Link WA, Ledo F, Torres B, Palczewska M, Madsen TM, Savignac M, Albar JP, Mellstrom B, Naranjo JR. Day-night changes in downstream regulatory element antagonist modulator/potassium channel interacting protein activity contribute to circadian gene expression in pineal gland. J Neurosci 24: 5346 –5355, 2004. 186. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T. STIM is a Ca2⫹ sensor essential for Ca2⫹-store-depletiontriggered Ca2⫹ influx. Curr Biol 15: 1235–1241, 2005. 187. Lipp P, Thomas D, Berridge MJ, Bootman MD. Nuclear calcium signalling by individual cytoplasmic calcium puffs. EMBO J 16: 7166 –7173, 1997. 188. Lopez JJ, Salido GM, Pariente JA, Rosado JA. Interaction of STIM1 with endogenously expressed human canonical TRP1 upon depletion of intracellular Ca2⫹ stores. J Biol Chem 281: 28254 – 28264, 2006. 189. Lu J, McKinsey TA, Nicol RL, Olson EN. Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci USA 97: 4070 – 4075, 2000. 190. Lu J, McKinsey TA, Zhang CL, Olson EN. Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6: 233–244, 2000. 191. Lui PP, Kong SK, Kwok TT, Lee CY. The nucleus of HeLa cell contains tubular structures for Ca2⫹ signalling. Biochem Biophys Res Commun 247: 88 –93, 1998. 192. Luik RM, Lewis RS. New insights into the molecular mechanisms of store-operated Ca(2⫹) signaling in T cells. Trends Mol Med 13: 103–107, 2007. 193. Luik RM, Wu MM, Buchanan J, Lewis RS. The elementary unit of store-operated Ca2⫹ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol 174: 815– 825, 2006. Physiol Rev • VOL
445
194. Lynch J, Guo L, Gelebart P, Chilibeck K, Xu J, Molkentin JD, Agellon LB, Michalak M. Calreticulin signals upstream of calcineurin and MEF2C in a critical Ca(2⫹)-dependent signaling cascade. J Cell Biol 170: 37– 47, 2005. 195. Ma HT, Patterson RL, van Rossum DB, Birnbaumer L, Mikoshiba K, Gill DL. Requirement of the inositol trisphosphate receptor for activation of store-operated Ca2⫹ channels. Science 287: 1647–1651, 2000. 196. Macian F, Garcia-Rodriguez C, Rao A. Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun. EMBO J 19: 4783– 4795, 2000. 197. Malgaroli A, Milani D, Meldolesi J, Pozzan T. Fura-2 measurement of cytosolic free Ca2⫹ in monolayers and suspensions of various types of animal cells. J Cell Biol 105: 2145–2155, 1987. 198. Mammucari C, Tommasi di Vignano A, Sharov AA, Neilson J, Havrda MC, Roop DR, Botchkarev VA, Crabtree GR, Dotto GP. Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control. Dev Cell 8: 665– 676, 2005. 199. Mansuy IM, Mayford M, Jacob B, Kandel ER, Bach ME. Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92: 39 – 49, 1998. 200. Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenberg ME. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286: 785–790, 1999. 201. Mao Z, Wiedmann M. Calcineurin enhances MEF2 DNA binding activity in calcium-dependent survival of cerebellar granule neurons. J Biol Chem 274: 31102–31107, 1999. 202. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302: 890 – 893, 2003. 203. Massari ME, Murre C. Helix-loop-helix proteins: regulators of transcription in eukaryotic organisms. Mol Cell Biol 20: 429 – 440, 2000. 204. Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2: 599 – 609, 2001. 205. McKenzie GJ, Stevenson P, Ward G, Papadia S, Bading H, Chawla S, Privalsky M, Hardingham GE. Nuclear Ca2⫹ and CaM kinase IV specify hormonal- and Notch-responsiveness. J Neurochem 93: 171–185, 2005. 206. McKinsey TA, Zhang CL, Olson EN. Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci USA 97: 14400 –14405, 2000. 207. Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D. NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6: 1072–1078, 2003. 208. Mellstrom B, Naranjo JR. Mechanisms of Ca(2⫹)-dependent transcription. Curr Opin Neurobiol 11: 312–319, 2001. 209. Mellstrom B, Torres B, Link WA, Naranjo JR. The BDNF gene: exemplifying complexity in Ca2⫹-dependent gene expression. Crit Rev Neurobiol 16: 43– 49, 2004. 210. Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem 281: 24979 –24990, 2006. 211. Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NFkappaB activation. Science 278: 860 – 866, 1997. 212. Merrill MA, Chen Y, Strack S, Hell JW. Activity-driven postsynaptic translocation of CaMKII. Trends Pharmacol Sci 26: 645– 653, 2005. 213. Metsis M, Timmusk T, Arenas E, Persson H. Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad Sci USA 90: 8802– 8806, 1993. 214. Michalak M, Burns K, Andrin C, Mesaeli N, Jass GH, Busaan JL, Opas M. Endoplasmic reticulum form of calreticulin modulates glucocorticoid-sensitive gene expression. J Biol Chem 271: 29436 –29445, 1996.
88 • APRIL 2008 •
www.prv.org
446
MELLSTRO¨M ET AL.
215. Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, Kouzarides T. HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J 18: 5099 –5107, 1999. 216. Miskin JE, Abrams CC, Dixon LK. African swine fever virus protein A238L interacts with the cellular phosphatase calcineurin via a binding domain similar to that of NFAT. J Virol 74: 9412–9420, 2000. 217. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93: 215–228, 1998. 218. Monticelli S, Rao A. NFAT1 and NFAT2 are positive regulators of IL-4 gene transcription. Eur J Immunol 32: 2971–2978, 2002. 219. Munch G, Bolck B, Karczewski P, Schwinger RH. Evidence for calcineurin-mediated regulation of SERCA 2a activity in human myocardium. J Mol Cell Cardiol 34: 321–334, 2002. 220. Nairn AC, Hemmings HC Jr, Walaas SI, Greengard P. DARPP-32 and phosphatase inhibitor-1, two structurally related inhibitors of protein phosphatase-1, are both present in striatonigral neurons. J Neurochem 50: 257–262, 1988. 221. Nakai J, Dirksen RT, Nguyen HT, Pessah IN, Beam KG, Allen PD. Enhanced dihydropyridine receptor channel activity in the presence of ryanodine receptor. Nature 380: 72–75, 1996. 222. Naranjo JR, Mellstrom B. Split personality of transcription factors inside and outside the nuclear border. Sci STKE 2007: pe5, 2007. 223. Nathanson MH, Fallon MB, Padfield PJ, Maranto AR. Localization of the type 3 inositol 1,4,5-trisphosphate receptor in the Ca2⫹ wave trigger zone of pancreatic acinar cells. J Biol Chem 269: 4693– 4696, 1994. 224. Naya FJ, Black BL, Wu H, Bassel-Duby R, Richardson JA, Hill JA, Olson EN. Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nat Med 8: 1303– 1309, 2002. 225. Nemer G, Nemer M. Cooperative interaction between GATA5 and NF-ATc regulates endothelial-endocardial differentiation of cardiogenic cells. Development 129: 4045– 4055, 2002. 226. Newton AC. Protein kinase C: structure, function and regulation. J Biol Chem 270: 28495–28498, 1995. 227. Obrietan K, Impey S, Smith D, Athos J, Storm DR. Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274: 17748 –17756, 1999. 228. Odom AR, Stahlberg A, Wente SR, York JD. A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control. Science 287: 2026 –2029, 2000. 229. Oka T, Dai YS, Molkentin JD. Regulation of calcineurin through transcriptional induction of the calcineurin A beta promoter in vitro and in vivo. Mol Cell Biol 25: 6649 – 6659, 2005. 230. Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, Gill D, Ambudkar IS. Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx: evidence for similarities in store-operated and calcium release-activated calcium channel components. J Biol Chem 282: 9105–9116, 2007. 231. Onions J, Hermann S, Grundstrom T. A novel type of calmodulin interaction in the inhibition of basic helix-loop-helix transcription factors. Biochemistry 39: 4366 – 4374, 2000. 232. Osawa M, Tong KI, Lilliehook C, Wasco W, Buxbaum JD, Cheng HY, Penninger JM, Ikura M, Ames JB. Calcium-regulated DNA binding and oligomerization of the neuronal calcium-sensing protein, calsenilin/DREAM/KChIP3. J Biol Chem 276: 41005– 41013, 2001. 233. Ou XM, Lemonde S, Jafar-Nejad H, Bown CD, Goto A, Rogaeva A, Albert PR. Freud-1: a neuronal calcium-regulated repressor of the 5-HT1A receptor gene. J Neurosci 23: 7415–7425, 2003. 234. Oukka M, Ho IC, de la Brousse FC, Hoey T, Grusby MJ, Glimcher LH. The transcription factor NFAT4 is involved in the generation and survival of T cells. Immunity 9: 295–304, 1998. 235. Pan F, Sun L, Kardian DB, Whartenby KA, Pardoll DM, Liu JO. Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin. Nature 445: 433– 436, 2007. 236. Papadia S, Stevenson P, Hardingham NR, Bading H, Hardingham GE. Nuclear Ca2⫹ and the cAMP response element-binding Physiol Rev • VOL
237. 238.
239.
240.
241.
242.
243. 244.
245.
246.
247.
248.
249.
250.
251.
252.
253.
254.
255.
256. 257.
protein family mediate a late phase of activity-dependent neuroprotection. J Neurosci 25: 4279 – 4287, 2005. Parekh AB, Penner R. Store depletion and calcium influx. Physiol Rev 77: 901–930, 1997. Park MK, Ashby MC, Erdemli G, Petersen OH, Tepikin AV. Perinuclear, perigranular and sub-plasmalemmal mitochondria have distinct functions in the regulation of cellular calcium transport. EMBO J 20: 1863–1874, 2001. Patterson RL, Boehning D, Snyder SH. Inositol 1,4,5-trisphosphate receptors as signal integrators. Annu Rev Biochem 73: 437– 465, 2004. Pauly N, Knight MR, Thuleau P, van der Luit AH, Moreau M, Trewavas AJ, Ranjeva R, Mazars C. Control of free calcium in plant cell nuclei. Nature 405: 754 –755, 2000. Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, KoblanHuberson M, Lis A, Fleig A, Penner R, Kinet JP. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8: 771–773, 2006. Peng SL, Gerth AJ, Ranger AM, Glimcher LH. NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity 14: 13–20, 2001. Petersen OH. Localization and regulation of Ca2⫹ entry and exit pathways in exocrine gland cells. Cell Calcium 33: 337–344, 2003. Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ, Breuning MH. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376: 348 –351, 1995. Pflum MK, Tong JK, Lane WS, Schreiber SL. Histone deacetylase 1 phosphorylation promotes enzymatic activity and complex formation. J Biol Chem 276: 47733– 47741, 2001. Phan D, Rasmussen TL, Nakagawa O, McAnally J, Gottlieb PD, Tucker PW, Richardson JA, Bassel-Duby R, Olson EN. BOP, a regulator of right ventricular heart development, is a direct transcriptional target of MEF2C in the developing heart. Development 132: 2669 –2678, 2005. Philipp S, Strauss B, Hirnet D, Wissenbach U, Mery L, Flockerzi V, Hoth M. TRPC3 mediates T-cell receptor-dependent calcium entry in human T-lymphocytes. J Biol Chem 278: 26629 – 26638, 2003. Pradhan A, Liu Y. A multifunctional domain of the calciumresponsive transactivator (CREST) that inhibits dendritic growth in cultured neurons. J Biol Chem 280: 24738 –24743, 2005. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG. Orai1 is an essential pore subunit of the CRAC channel. Nature 443: 230 –233, 2006. Rakhilin SV, Olson PA, Nishi A, Starkova NN, Fienberg AA, Nairn AC, Surmeier DJ, Greengard P. A network of control mediated by regulator of calcium/calmodulin-dependent signaling. Science 306: 698 –701, 2004. Raman V, Blaeser F, Ho N, Engle DL, Williams CB, Chatila TA. Requirement for Ca2⫹/calmodulin-dependent kinase type IV/Gr in setting the thymocyte selection threshold. J Immunol 167: 6270 – 6278, 2001. Randriamampita C, Tsien RY. Emptying of intracellular Ca2⫹ stores releases a novel small messenger that stimulates Ca2⫹ influx. Nature 364: 809 – 814, 1993. Ranger AM, Grusby MJ, Hodge MR, Gravallese EM, de la Brousse FC, Hoey T, Mickanin C, Baldwin HS, Glimcher LH. The transcription factor NF-ATc is essential for cardiac valve formation. Nature 392: 186 –190, 1998. Ranger AM, Oukka M, Rengarajan J, Glimcher LH. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9: 627– 635, 1998. Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15: 707–747, 1997. Redmond L, Ghosh A. Regulation of dendritic development by calcium signaling. Cell Calcium 37: 411– 416, 2005. Redmond L, Kashani AH, Ghosh A. Calcium regulation of dendritic growth via CaM kinase IV and CREB-mediated transcription. Neuron 34: 999 –1010, 2002.
88 • APRIL 2008 •
www.prv.org
Ca2⫹-REGULATED GENE EXPRESSION 258. Ribar TJ, Rodriguiz RM, Khiroug L, Wetsel WC, Augustine GJ, Means AR. Cerebellar defects in Ca2⫹/calmodulin kinase IVdeficient mice. J Neurosci 20: RC107, 2000. 259. Rivas M, Mellstrom B, Naranjo JR, Santisteban P. Transcriptional repressor DREAM interacts with thyroid transcription factor-1 and regulates thyroglobulin gene expression. J Biol Chem 279: 33114 –33122, 2004. 260. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. STIM1, an essential and conserved component of store-operated Ca2⫹ channel function. J Cell Biol 169: 435– 445, 2005. 261. Rothermel B, Vega RB, Yang J, Wu H, Bassel-Duby R, Williams RS. A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J Biol Chem 275: 8719 – 8725, 2000. 262. Rothermel BA, McKinsey TA, Vega RB, Nicol RL, Mammen P, Yang J, Antos CL, Shelton JM, Bassel-Duby R, Olson EN, Williams RS. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 98: 3328 –3333, 2001. 263. Rothermel BA, Vega RB, Williams RS. The role of modulatory calcineurin-interacting proteins in calcineurin signaling. Trends Cardiovasc Med 13: 15–21, 2003. 264. Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder RG. Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J 16: 7091–7104, 1997. 264a.Ruiz-Gomez A, Mellström B, Tornero D, Morato E, Savignac M, Holguin H, Aurrekoetxea K, Gonzalez P, Gonzalez-Garcia C, Cena V, Mayor F Jr, Naranjo JR. GRK2-mediated phosphorylation of DREAM regulates membrane trafficking of Kv4.2 potassium channel. J Biol Chem 282: 1205–1215, 2007. 265. Ryeom S, Greenwald RJ, Sharpe AH, McKeon F. The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin. Nat Immunol 4: 874 – 881, 2003. 266. Saccani S, Natoli G. Dynamic changes in histone H3 Lys 9 methylation occurring at tightly regulated inducible inflammatory genes. Genes Dev 16: 2219 –2224, 2002. 267. Saijo K, Mecklenbrauker I, Santana A, Leitger M, Schmedt C, Tarakhovsky A. Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha. J Exp Med 195: 1647–1652, 2002. 268. Sala C, Rudolph-Correia S, Sheng M. Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons. J Neurosci 20: 3529 –3536, 2000. 269. Santella L, Carafoli E. Calcium signaling in the cell nucleus. FASEB J 11: 1091–1109, 1997. 270. Sanz C, Mellstrom B, Link WA, Naranjo JR, Fernandez-Luna JL. Interleukin 3-dependent activation of DREAM is involved in transcriptional silencing of the apoptotic Hrk gene in hematopoietic progenitor cells. EMBO J 20: 2286 –2292, 2001. 271. Savignac M, Pintado B, Gutierrez-Adan A, Palczewska M, Mellstrom B, Naranjo JR. Transcriptional repressor DREAM regulates T-lymphocyte proliferation and cytokine gene expression. EMBO J 24: 3555–3564, 2005. 272. Sawadogo M, Van Dyke MW, Gregor PD, Roeder RG. Multiple forms of the human gene-specific transcription factor USF. I. Complete purification and identification of USF from HeLa cell nuclei. J Biol Chem 263: 11985–11993, 1988. 273. Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, Sakahira H, Siegers K, Hayer-Hartl M, Hartl FU. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 15: 95–105, 2004. 273a.Schuman EM. Neurotrophin regulation of synaptic transmission. Curr Opin Neurobiol 9: 105–109, 1999. 274. Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H, Okamoto M, Montminy M. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119: 61–74, 2004. Physiol Rev • VOL
447
275. Scsucova S, Palacios D, Savignac M, Mellstrom B, Naranjo JR, Aranda A. The repressor DREAM acts as a transcriptional activator on Vitamin D and retinoic acid response elements. Nucleic Acids Res 33: 2269 –2279, 2005. 276. Shahbazian MD, Zoghbi HY. Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Curr Opin Neurol 14: 171–176, 2001. 277. Shen X, Xiao H, Ranallo R, Wu WH, Wu C. Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science 299: 112–114, 2003. 278. Sheng M, Thompson MA, Greenberg ME. CREB: a Ca(2⫹)regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252: 1427–1430, 1991. 279. Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A. Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20: 727–740, 1998. 280. Silva AJ, Stevens CF, Tonegawa S, Wang Y. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science 257: 201–206, 1992. 280a.Silverstein RA, Ekwall K. Sin3: a flexible regulator of global gene expression and genome stability. Curr Genet 47: 1–17, 2005. 281. Sirito M, Lin Q, Maity T, Sawadogo M. Ubiquitous expression of the 43- and 44-kDa forms of transcription factor USF in mammalian cells. Nucleic Acids Res 22: 427– 433, 1994. 282. Sohrabji F, Miranda RC, Toran-Allerand CD. Identification of a putative estrogen response element in the gene encoding brainderived neurotrophic factor. Proc Natl Acad Sci USA 92: 11110 – 11114, 1995. 283. Soloaga A, Thomson S, Wiggin GR, Rampersaud N, Dyson MH, Hazzalin CA, Mahadevan LC, Arthur JS. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J 22: 2788 –2797, 2003. 284. Solymar DC, Agarwal S, Bassing CH, Alt FW, Rao A. A 3⬘ enhancer in the IL-4 gene regulates cytokine production by Th2 cells and mast cells. Immunity 17: 41–50, 2002. 285. Sparrow DB, Miska EA, Langley E, Reynaud-Deonauth S, Kotecha S, Towers N, Spohr G, Kouzarides T, Mohun TJ. MEF-2 function is modified by a novel co-repressor, MITR. EMBO J 18: 5085–5098, 1999. 286. Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 97: 6763– 6768, 2000. 287. Steger DJ, Haswell ES, Miller AL, Wente SR, O’Shea EK. Regulation of chromatin remodeling by inositol polyphosphates. Science 299: 114 –116, 2003. 288. Straub SV, Giovannucci DR, Yule DI. Calcium wave propagation in pancreatic acinar cells: functional interaction of inositol 1,4,5trisphosphate receptors, ryanodine receptors, mitochondria. J Gen Physiol 116: 547–560, 2000. 289. Strynadka NC, James MN. Crystal structures of the helix-loophelix calcium-binding proteins. Annu Rev Biochem 58: 951–998, 1989. 290. Su TT, Guo B, Kawakami Y, Sommer K, Chae K, Humphries LA, Kato RM, Kang S, Patrone L, Wall R, Teitell M, Leitges M, Kawakami T, Rawlings DJ. PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol 3: 780 –786, 2002. 291. Su Z, Csutora P, Hunton D, Shoemaker RL, Marchase RB, Blalock JE. A store-operated nonselective cation channel in lymphocytes is activated directly by Ca2⫹ influx factor and diacylglycerol. Am J Physiol Cell Physiol 280: C1284 –C1292, 2001. 292. Sugars KL, Brown R, Cook LJ, Swartz J, Rubinsztein DC. Decreased cAMP response element-mediated transcription: an early event in exon 1 and full-length cell models of Huntington’s disease that contributes to polyglutamine pathogenesis. J Biol Chem 279: 4988 – 4999, 2004. 293. Sun L, Youn HD, Loh C, Stolow M, He W, Liu JO. Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 8: 703–711, 1998.
88 • APRIL 2008 •
www.prv.org
448
MELLSTRO¨M ET AL.
294. Sun XX, Hodge JJ, Zhou Y, Nguyen M, Griffith LC. The eag potassium channel binds and locally activates calcium/calmodulindependent protein kinase II. J Biol Chem 279: 10206 –10214, 2004. 295. Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, Annes J, Petrzilka D, Kupfer A, Schwartzberg PL, Littman DR. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature 404: 402– 407, 2000. 296. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 21: 713–758, 2003. 297. Tabuchi A, Sakaya H, Kisukeda T, Fushiki H, Tsuda M. Involvement of an upstream stimulatory factor as well as cAMPresponsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem 277: 35920 –35931, 2002. 298. Takeuchi Y, Miyamoto E, Fukunaga K. Analysis on the promoter region of exon IV brain-derived neurotrophic factor in NG108 –15 cells. J Neurochem 83: 67–79, 2002. 299. Tanabe T, Beam KG, Powell JA, Numa S. Restoration of excitation-contraction coupling and slow calcium current in dysgenic muscle by dihydropyridine receptor complementary DNA. Nature 336: 134 –139, 1988. 300. Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca2⫹ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20: 709 –726, 1998. 301. Tao X, West AE, Chen WG, Corfas G, Greenberg ME. A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron 33: 383–395, 2002. 302. Thomson S, Clayton AL, Hazzalin CA, Rose S, Barratt MJ, Mahadevan LC. The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase. EMBO J 18: 4779 – 4793, 1999. 303. Thorn P, Lawrie AM, Smith PM, Gallacher DV, Petersen OH. Local and global cytosolic Ca2⫹ oscillations in exocrine cells evoked by agonists and inositol trisphosphate. Cell 74: 661– 668, 1993. 304. Timmerman LA, Clipstone NA, Ho SN, Northrop JP, Crabtree GR. Rapid shuttling of NF-AT in discrimination of Ca2⫹ signals and immunosuppression. Nature 383: 837– 840, 1996. 305. Timmusk T, Lendahl U, Funakoshi H, Arenas E, Persson H, Metsis M. Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, neuronal activityinduced expression in transgenic mice. J Cell Biol 128: 185–199, 1995. 306. Timmusk T, Palm K, Lendahl U, Metsis M. Brain-derived neurotrophic factor expression in vivo is under the control of neuronrestrictive silencer element. J Biol Chem 274: 1078 –1084, 1999. 307. Tinel H, Cancela JM, Mogami H, Gerasimenko JV, Gerasimenko OV, Tepikin AV, Petersen OH. Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca(2⫹) signals. EMBO J 18: 4999 –5008, 1999. 308. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387: 677– 684, 1997. 309. Trushin SA, Pennington KN, Algeciras-Schimnich A, Paya CV. Protein kinase C and calcineurin synergize to activate IkappaB kinase and NF-kappaB in T lymphocytes. J Biol Chem 274: 22923– 22931, 1999. 310. Trushin SA, Pennington KN, Carmona EM, Asin S, Savoy DN, Billadeau DD, Paya CV. Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes. Mol Cell Biol 23: 7068 –7081, 2003. 311. Tsai SC, Seto E. Regulation of histone deacetylase 2 by protein kinase CK2. J Biol Chem 277: 31826 –31833, 2002. 312. Tsytsykova AV, Goldfeld AE. Nuclear factor of activated T cells transcription factor NFATp controls superantigen-induced lethal shock. J Exp Med 192: 581–586, 2000. 313. Vega RB, Bassel-Duby R, Olson EN. Control of cardiac growth and function by calcineurin signaling. J Biol Chem 278: 36981– 36984, 2003. Physiol Rev • VOL
314. Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 22: 1313–1324, 2003. 315. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, KoblanHuberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP. CRACM1 is a plasma membrane protein essential for store-operated Ca2⫹ entry. Science 312: 1220 –1223, 2006. 316. Vong LH, Ragusa MJ, Schwarz JJ. Generation of conditional Mef2cloxP/loxP mice for temporal- and tissue-specific analyses. Genesis 43: 43– 48, 2005. 317. Wakim BT, Aswad GD. Ca(2⫹)-calmodulin-dependent phosphorylation of arginine in histone 3 by a nuclear kinase from mouse leukemia cells. J Biol Chem 269: 2722–2727, 1994. 318. Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th’ng J, Han J, Yang XJ. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol Cell Biol 19: 7816 –7827, 1999. 319. Waxham MN, Grotta JC, Silva AJ, Strong R, Aronowski J. Ischemia-induced neuronal damage: a role for calcium/calmodulindependent protein kinase II. J Cereb Blood Flow Metab 16: 1– 6, 1996. 320. Wei F, Qiu CS, Liauw J, Robinson DA, Ho N, Chatila T, Zhuo M. Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat Neurosci 5: 573–579, 2002. 321. West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, Takasu MA, Tao X, Greenberg ME. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci USA 98: 11024 –11031, 2001. 322. Westenbroek RE, Hell JW, Warner C, Dubel SJ, Snutch TP, Catterall WA. Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron 9: 1099 – 1115, 1992. 323. Whitlock JP Jr, Galeazzi D, Schulman H. Acetylation and calcium-dependent phosphorylation of histone H3 in nuclei from butyrate-treated HeLa cells. J Biol Chem 258: 1299 –1304, 1983. 324. Winder DG, Mansuy IM, Osman M, Moallem TM, Kandel ER. Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin. Cell 92: 25–37, 1998. 325. Wu JY, Gonzalez-Robayna IJ, Richards JS, Means AR. Female fertility is reduced in mice lacking Ca2⫹/calmodulin-dependent protein kinase IV. Endocrinology 141: 4777– 4783, 2000. 326. Wu JY, Ribar TJ, Cummings DE, Burton KA, McKnight GS, Means AR. Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nat Genet 25: 448 – 452, 2000. 327. Wu MM, Buchanan J, Luik RM, Lewis RS. Ca2⫹ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174: 803– 813, 2006. 328. Wu Y, Colbran RJ, Anderson ME. Calmodulin kinase is a molecular switch for cardiac excitation-contraction coupling. Proc Natl Acad Sci USA 98: 2877–2881, 2001. 329. Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC. Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells. Proc Natl Acad Sci USA 103: 14379 –14384, 2006. 330. Xanthoudakis S, Viola JP, Shaw KT, Luo C, Wallace JD, Bozza PT, Luk DC, Curran T, Rao A. An enhanced immune response in mice lacking the transcription factor NFAT1. Science 272: 892– 895, 1996. 331. Yang J, Hurley TD, DePaoli-Roach AA. Interaction of inhibitor-2 with the catalytic subunit of type 1 protein phosphatase Identification of a sequence analogous to the consensus type 1 protein phosphatase-binding motif. J Biol Chem 275: 22635–22644, 2000. 332. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res 87: E61– 68, 2000. 333. Yang T, Poovaiah BW. Calcium/calmodulin-mediated signal network in plants. Trends Plant Sci 8: 505–512, 2003.
88 • APRIL 2008 •
www.prv.org
Ca2⫹-REGULATED GENE EXPRESSION 334. Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443: 226 –229, 2006. 335. Yoshida H, Nishina H, Takimoto H, Marengere LE, Wakeham AC, Bouchard D, Kong YY, Ohteki T, Shahinian A, Bachmann M, Ohashi PS, Penninger JM, Crabtree GR, Mak TW. The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production. Immunity 8: 115–124, 1998. 336. Youn HD, Chatila TA, Liu JO. Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. EMBO J 19: 4323– 4331, 2000. 337. Youn HD, Grozinger CM, Liu JO. Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4. J Biol Chem 275: 22563–22567, 2000. 338. Youn HD, Sun L, Prywes R, Liu JO. Apoptosis of T cells mediated by Ca2⫹-induced release of the transcription factor MEF2. Science 286: 790 –793, 1999. 339. Zhang BW, Zimmer G, Chen J, Ladd D, Li E, Alt FW, Wiederrecht G, Cryan J, O’Neill EA, Seidman CE, Abbas AK, Seidman JG. T cell responses in calcineurin A alpha-deficient mice. J Exp Med 183: 413– 420, 1996. 340. Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD. Genome-wide RNAi screen of Ca(2⫹) influx identifies genes that regulate Ca(2⫹) release-activated Ca(2⫹) channel activity. Proc Natl Acad Sci USA 103: 9357–9362, 2006.
Physiol Rev • VOL
449
341. Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD. STIM1 is a Ca2⫹ sensor that activates CRAC channels and migrates from the Ca2⫹ store to the plasma membrane. Nature 437: 902–905, 2005. 342. Zhang X, Odom DT, Koo SH, Conkright MD, Canettieri G, Best J, Chen H, Jenner R, Herbolsheimer E, Jacobsen E, Kadam S, Ecker JR, Emerson B, Hogenesch JB, Unterman T, Young RA, Montminy M. Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, target gene activation in human tissues. Proc Natl Acad Sci USA 102: 4459 – 4464, 2005. 343. Zhang X, Ozawa Y, Lee H, Wen YD, Tan TH, Wadzinski BE, Seto E. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev 19: 827– 839, 2005. 344. Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E. Loss of huntingtinmediated BDNF gene transcription in Huntington’s disease. Science 293: 493– 498, 2001. 345. Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35: 76 – 83, 2003.
88 • APRIL 2008 •
www.prv.org
