Control of Stress-Regulated Gene Expression and Longevity by the ...

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Control of Stress-Regulated Gene Expression and Longevity by the Sch9 Protein Kinase Abstract

*Correspondence to: Markus Proft; Instituto de Biología Molecular y Celular de Plantas; Universidad Politécnica Valencia; Ingeniero Fausto Elio s/n; Valencia E-46022 Spain; Tel.: 34.96.387.9375; Fax: 34.96.387.7859; Email: mproft@ ibmcp.upv.es Spain

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The work of the authors is supported by grants from Ministerio de Educación y Ciencia (BFU2005-01714) and from Generalitat Valenciana (Consellería de Empresa, Universidad y Ciencia; GV06/041 and ACOMP07-198).

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Sch9, life span, Sko1, osmostress, chromatin, transcriptional activation, TOR

All eukaryotic cells have developed sophisticated mechanisms to coordinate cell growth and cell division with the availability of the required nutrients and other environmental conditions. Generally, nutrient signaling pathways stimulate cell biomass production and progression through the cell cycle upon nutrient abundance. However, upon nutrient deprivation or under adverse environmental conditions, cell growth and cell cycle progres‑ sion stop to favor stress adaptation and survival. Cells with an altered coordination of growth versus stress adaptation show phenotypes related to stress resistance and life span. Yeast cells serve as a powerful model to decipher the signaling pathways involved in the adjustment of growth and life span with external stimuli like nutrients and stress.1 The quantitation of the time cells survive in stationary phase (chronological life span, CLS) turned out to be a particularly useful parameter to assay life span. Large scale screenings of yeast mutants with an extended life span identified evolutionarily conserved nutrient signaling pathways as important determinants of life span. Specifically, mutants in the Ras and TOR (target of rapamycin) pathways as well as deletion of the Sch9 kinase increased CLS and stress resistance.2‑4 Importantly, loss of Ras, Sch9 and TOR functions also extend the number of daughter cells produced by a single mother cell before its death (replicative life span).5,6 Important pieces of information regarding the nutrient dependent regulation of Sch9 activity or downstream effects and effectors of the kinase were not known. Very recent reports shed light on the functions of Sch9 in nutrient‑ and stress‑dependent regu‑ latory events; Sch9 is a direct target of the Tor1 kinase under favorable growth conditions and Sch9, via the Sko1 transcription factor, can activate stress gene expression upon high osmolarity.7,8 The Sch9 kinase has been previously characterized as important for the coordination of cell growth and nutrient availability by activating ribosomal protein (RP) and ribosome biogenesis (Ribi) genes (the so called RP and Ribi regulons).9 These data placed Sch9 phenotypically downstream of the TOR signaling pathway, the central coordinator of cell growth and nutrition.10,11 Urban and coworkers now demonstrate that Sch9 is directly phosphorylated by TORC1 (TOR complex 1) at multiple C‑terminal residues.7 These data imply that under optimal growth conditions (activation of the TOR pathway) the Tor1 kinase directly modifies Sch9 to activate the expression of the RP and Ribi regulons. As cells face nutrient limitation or stress, signaling through TOR decreases and Sch9 would no longer be modified by Tor1. This could explain how the cell adjusts ribosome synthesis at the transcriptional level by the direct interplay of the two signaling kinases, Tor1 and Sch9. However, the molecular events that link TOR‑modulated Sch9 activity to the stimulated transcription of RP and Ribi genes remain speculative. A recent report

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/4792

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Original manuscript submitted: 07/23/07 Manuscript accepted: 07/23/07

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Instituto de Biología Molecular y Celular de Plantas; Universidad Politécnica Valencia; Valencia, Spain

Cell growth and progression through the cell cycle is finely tuned by nutrient avail‑ ability and stress in eukaryotic cells. In yeast, the Sch9 protein kinase has been identified as a central regulator of longevity and stress resistance. Recent work revealed that Sch9 plays critical roles in transcriptional activation dependent on the environmental condi‑ tions. Favorable growth conditions stimulate the expression of genes related to ribosomal function by direct targeting of Sch9 by the TOR kinase, whereas under osmostress condi‑ tions, Sch9 plays a direct role in the activation of stress defense genes. At least upon stress, Sch9 seems to activate transcription directly at the chromatin structure. Therefore we speculate that targeting of the kinase to chromatin might coordinate transcription dependent on environmental stimuli and be responsible for the functions of Sch9 in life span regulation and adaptation to stress.

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Amparo Pascual-Ahuir Markus Proft*

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Figure 1. Schematic overview of the functions of Sch9 in transcriptional regu‑ lation. Upon favorable growth conditions (nutrient abundance), activation of the TOR pathway results in phosphorylation of Sch9 by the Tor1 kinase at multiple sites. Phosphorylated Sch9 is needed for the stimulated expression of ribosomal protein (RP) and ribosomal biogenesis (Ribi) genes. Transcriptional up‑regulation involves the stable association of Tor1 to chromatin. The nature and functions of specific transcription factors (TF) in the activation of RP and Ribi genes by Tor1 and Sch9 are not known. Hyperosmotic stress nega‑ tively affects signaling through the TOR pathway and transiently activates the Hog1 MAP kinase. The transcriptional response to osmostress involves the recruitment of the Sch9 and Hog1 kinases to defense gene promoters. Both kinases phosphorylate the Sko1 transcriptional repressor/activator. Sko1 is necessary to target Hog1 and Sch9 to the chromatin of osmostress‑responsive genes, where they play important roles in the transcriptional adaptation.

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shows that at least a fraction of Tor1 kinase is localized in the nucleus and, more importantly, that Tor1 associates with the 35S ribosomal DNA promoter in vivo in a nutrient dependent manner.12 Although the mechanism of Tor1 recruitment to rDNA promoters has to be determined yet, it can be concluded that the Tor1 kinase has much more direct functions in stimulating ribosomal gene transcription within the chromatin structure than previously anticipated. Given that Tor1 contacts Sch9 directly and both kinases are activators of RP and Ribi gene transcription, both molecules could coordinately act in the chromatin context of the activated genes. If this model is true, the nutrient dependent targeting to transcriptionally active loci (already shown for Tor1, speculative for Sch9) of the two kinases could be an important regulatory step for transcriptional activation upon favor‑ able growth conditions. Furthermore, it will be of great interest to investigate whether specific transcriptional activators (Rap1, Ifh1, Fhl1) bound at ribosomal protein gene promoters function in the recruitment of regulatory kinases. Our results demonstrate that, additionally to the activator func‑ tion under optimal growth conditions, Sch9 directly stimulates the expression of defense genes upon hyperosmotic stress.8 Sch9 acts through the transcriptional repressor/activator Sko1, which is also targeted by the stress activated MAP kinase Hog1.13 Sko1 not only is a direct downstream effector and phosphorylation target of the Sch9 and Hog1 kinases, but it transiently recruits both molecules to some osmoresponsive promoters exclusively upon stress.8,14 Moreover, the association of both signaling kinases is mutually interdependent.8 Based on these results we propose that Sch9, together with the Hog1 MAPK, activates osmostress responsive transcription right at the chromatin structure. Taken together, it seems that Sch9 activates distinct sets of target genes depending on the growth conditions (see Fig. 1). What might be the mechanisms to direct Sch9 activity towards one set of target genes or another? In the case of osmolarity‑regulated genes, we have identified the selective recruitment of the kinase to target promoters (for example GRE2 or CTT1) as a component of Sch9 regulation.8 On the other hand, Sch9 is a constitutively active transcriptional activator, because it apparently does not depend on growth conditions to stimulate transcription when artificially teth‑ ered to a promoter.8,15 Thus it might be the selective recruitment of Sch9 to chromatin what determines the specificity of gene expression. In this scenario, transcription factors like Sko1 or others yet to be determined can serve to recruit the kinase to promoters. In general, signaling kinases in eukaryotic cells can function as chromatin‑associ‑ ated enzymes in transcriptional activation.16 It will be of great interest to decipher the highly dynamic and probably complex recruitment events of such kinases in response to environmental stimuli. In the model discussed here we have to imply multiple kinases which act at the chromatin level: Upon favorable growth conditions, the nutrient regulated Tor1 and protein kinase A subunits associate with actively transcribed genes like ribosomal protein genes.12,17 Sch9 is a good candidate for another contributing kinase under these conditions. Osmostress favors the transient association of at least two kinases, the Hog1 MAPK and Sch9, with stress activated genes.8 In the future, genome‑wide location analysis will be of great help to identify the dynamics of the recruitment of the kinases involved in the adaptation of gene expression to nutrients and stress. What are the upstream events regulating Sch9 activity? Under optimal growth conditions Sch9 would be maintained in its phos‑ phorylated state by the activated TORC1 complex. Phosphorylation

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decreases under adverse conditions, including osmostress, as signaling through TOR diminishes.7 The function of Sch9 in osmostress regulated transcription depends on the HOG pathway, which is specifically activated upon osmotic stress. Sch9 is not recruited to stress‑activated loci in the absence of Hog1.8 Although a signaling input from HOG to Sch9 has not reported yet, it might be the combination of TOR and HOG modulation of Sch9 which is important for its specificity. From the studies in yeast we can learn that a central regulator of cell growth in response to nutrient availability like the Sch9 kinase has much more direct functions in transcriptional activation than previously thought. These functions depend on the physiological state of the yeast cell. Thus, the lack of Sch9 function can cause opposite phenotypes regarding oxidative and osmotic stress resis‑ tance, namely hypersensitivity in dividing cells under acute stress and resistance in stationary non-dividing cells.2,8 A complex scenario of both negatively and positively regulated genes has been revealed for Sch9 by transcriptional profiling.18 The function of Sch9 is of great scientific interest as mutants in the TOR pathway (including Sch9 orthologs) show an increased life span in higher eucaryotes like Caenorhabditis elegans or Drosophila melanogaster.19,20 We predict that yeast will continue to serve as a powerful model to decipher the kinase networks at the chromatin responsible for the activation of transcriptional programs upon environmental stress.

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Control of Gene Expression and Longevity by the Sch9 Kinase

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