Macrophage Migration Inhibitory Factor Coordinates DNA Damage ...

[Cell Cycle 6:9, 1030-1034, 1 May 2007]; ©2007 Landes Bioscience

Perspective

Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle Alice Nemajerova1 Ute M. Moll1 Oleksi Petrenko1 Günter Fingerle-Rowson2,*

Abstract

IST RIB

1Department of Pathology; State University of New York at Stony Brook; Stony Brook, New York USA

UT E

.

Proper repair of DNA damage is critical for protecting genomic stability, cellular viability and suppression of tumorigenesis. Both p53‑dependent and p53‑independent pathways have evolved to coordinate the cellular response following DNA damage. In this review, we highlight the importance of the ubiquitously expressed protein macro‑ phage migration inhibitory factor (MIF) for an appropriate response to DNA damage. We discuss the mechanisms by which MIF affects the activity of the ubiquitin‑proteasome system, and how this impacts on the integrity of the genome and on cancer.

2University

*Correspondence to: Günter Fingerle-Rowson; University Hospital Cologne; Medical Clinic I; LFI, Level 4, Room 704; Kerpenerstr. 62; 50924 Cologne, Germany; Tel.: +49 .0221.478.87234; Fax: +49.0221.478.6383; Email: [email protected]

Proper regulation of cell proliferation is critical for normal development and cancer prevention. Cells continuously encounter DNA damage caused by base alterations due to oxidative stress from endogenous ROS production or by genotoxic noxae from the environment such as ultraviolet and ionizing irradiation. Failure to properly repair DNA can lead to various disorders, including enhanced rates of tumor development.1,2 To avoid these outcomes, cells with damaged genomes involve an elaborate network of p53‑dependent and p53‑independent checkpoint pathways aimed to delay cell cycle progression, thereby allowing DNA repair.1 Cancer development frequently selects for loss of p53 function and hence for loss of the G1 checkpoint.3 Recent studies demonstrated that mutations compromising the G2M checkpoint are also oncogenic.1,4 However, the G2M response elicits signals that not only trigger growth arrest or apoptosis, but also promote DNA repair.5 Checkpoints alone cannot safeguard the cell, but depend on proper routing to the cell cycle shut‑off machinery. Therefore, the checkpoint network must not only sense damage, but also spread signals to downstream effectors that execute the cell division shut‑off program. This is achieved by activating stress kinases (ATM, ATR, Chk1, Chk2), which in turn mark key cell cycle regulators by phosphorylation which leads to their ubiquitylation and subsequent destruction by the proteasome machinery.4 Importantly, cancer cells must retain sufficient G2M checkpoint function in order to survive adverse conditions that could further destabilize their genome, causing mitotic catastrophe and cell death.1,2

Key words

IEN

macrophage migration inhibitory factor, MIF, DNA damage, p53, proteasome, Jab1, SCF

CE

Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=4163

.D

ON

Original manuscript submitted: 03/19/07 Manuscript accepted: 03/20/07

Introduction

OT D

Hospital Cologne; Medical Clinic I; Hematology and Oncology; Cologne, Germany

Acknowledgements

©

20

07

LA

ND

ES

BIO

SC

This work was supported by the Koeln Fortune Program of the Medical Faculty of Cologne University (G.F-R.), the German Research Council DFG grant Fi 712/2-1 (G.F-R.), the Jose-Carreras Leukemia Foundation (G.F-R.), Philip Morris International (U.M.M.), the National Cancer Institute (U.M.M.) and by Stony Brook Cancer Center (O.P.).

1030

The Proteasome: The Executive of Cell Cycle Control Normal cell cycle control is a multilayer process. The immediate events, i.e., DNA synthesis and chromosome segregation, are qualitatively controlled by protein kinase complexes during intra S‑phase and mitotic checkpoints.6,7 Progression through the cycle depends on the activity of cyclin‑dependent kinases (CDKs), which act in conjunction with their corresponding positive “molecular clocks”, the cyclins, and conversely are slowed down by CDK inhibitors (CKIs). The protein levels of cyclins, CKIs and other core cell cycle regulators are quantitatively controlled by the ubiquitin‑proteasome system (UPS). Of note, CDKs and ubiquitin ligases reciprocally regulate each other, resulting in complex feedback loops.8 A typical human cell contains about 30,000 proteasomes that work at an adjustable speed. Thus, it has been calculated that in resting cells approximately 5 x 105 protein molecules per minute are processed by proteasomes, and this number may increase to 2 x 106 molecules per minute in actively dividing cells.9 Two principal E3 ubiquitin ligases, the anaphase‑promoting/cyclosome complex (APC/C) and the Skp1‑Cullin1‑F‑box (SCF) complex, have recently emerged as key Cell Cycle

2007; Vol. 6 Issue 9

MIF Coordinates DNA Damage Response with Proteasomal Activity

OT D

IST RIB

UT E

.

In order to grasp the mechanism underlying the intriguing functional interaction between MIF and p53, we analyzed the consequences of MIF deletion in mice. To this end, we compared the DNA damage response in lymphoma cells derived from p53‑/‑ and MIF‑/‑p53‑/‑ mice.43 Strikingly, MIF/p53 double deficient cells clearly possessed a dysfunctional G2M checkpoint, since they continued to proliferate under conditions of DNA damage, which coincided with sharply increased rates of apoptosis. Thus, apparently one essential function of MIF was not to merely promote cell survival, but also to coordinate a second line of cellular defence against DNA damage— after the protective p53 barrier had been eliminated. This prompted us to ask a number of further questions, most importantly— through which mechanism did MIF achieve this effect? One of the major biological responses to DNA damage or stalled replication is induction of the Chk1‑ and Chk2‑dependent checkpoints that inhibit proliferation of cells with damaged templates.4 Among the key functional targets/substrates of Chk1/Chk2 regulation is the family of Cdc25 protein phosphatases (Cdc25 A‑C), which play a critical role in activating Cdk2 and Cdk1 kinase complexes.2 The protein levels of Cdc25A are controlled by ubiquitin‑dependent proteasomal degradation. The APC/C mediates degradation of Cdc25A starting at the end of mitosis throughout the G1 phase, while the SCF complex plays a critical role in Cdc25A degradation in response to DNA damage.10,44 �� Importantly, �� we found that�� loss of MIF uncouples Chk1/Chk2 checkpoints from proteasomal degradation of �� Cdc25A under conditions of DNA damage.43 �� Moreover, MIF‑deficiency imposes similar defects on the proper degradation of �� several other important cell cycle regulators such as �� Cyclin A2, E2F1 and DP1.43 Because MIF directly binds to Jab1 and prevents it from interacting with proteins targeted by CSN, notably the cullins, it appeared that the unrestricted deneddylating activity of Jab1 and therefore the ensuing dysfunction of SCF were collectively responsible for the defects seen in MIF‑deficient cells. Indeed, we found that in MIF‑deficient cells a large proportion of Cul1 was deneddylated and therefore remained sequestered by inhibitory Cand1.43 W�� e also showed that �� DNA damage and stalled replication induce coordinate activity of Chk1 and the SCF complex in wild type cells. This is achieved by a direct phosphorylation of Cul1 by Chk1. This important step of Cul1 activation is severely impaired in MIF‑deficient cells.43 Collectively, these data imply that regulation of Jab1 by MIF is required to sustain a pool of SCF that is devoid of interaction with inhibitory Cand1�� but instead is available for interaction with Chk1 (Fig. 1).

.D

MIF Controls Proteasomal Activity via the Deneddylating Activity of Jab1

MIF is an Essential Component of the G2M DNA Damage Checkpoint Response

ON

cell cycle regulators.10,11 The APC/C is active from mid M‑phase to the end of G1‑phase, while SCFs are active from late G1 to early M‑phase. Thus, SCF complexes appear to be more versatile and fulfill critical functions within the G2M checkpoint.11 This is also reflected in the fact that components of the SCF complex show far more genetic alterations than those of APC/C in human cancers.11 The SCF complex consists of three invariable components— Rbx1, Cul1 (scaffold protein) and Skp1 (adaptor protein)—as well as one protein from the F‑box family, which is responsible for substrate recognition.12 To date, about 70 F‑box proteins have been identified in humans.13 Together, the Rbx1 and Cul1 subunits form the catalytic core of SCF (Fig. 1). The activity of the catalytic core is stimulated by attachment of a ubiquitin‑like protein called Nedd8 to conserved lysines in the cullin‑homology domain.14 This step, which presumably involves Rbx1, is preserved from yeast to mammals and stimulates subsequent recruitment of E2 enzymes. Conversely, deneddylation of cullins through the CSN/COP9 signalosome, with its Jab1/CSN5 subunit directly cleaving off Nedd8, decreases E2 recruitment.15,16 In addition, CSN recruits a deubiquitylase Ubp12, which counteracts the intrinsic ubiquitin‑polymerizing activity of SCF.17 Importantly, deneddylated cullins are sequestered by inhibitory Cand1 (Fig. 1).18,19 Thus, it was proposed that SCF activity is sustained by dynamic cycles of assembly and disassembly, where both Cand1 and CSN play an essential negative role.20 It is important to note that deregulation of SCF activity greatly promotes cancer development.11

©

20

07

LA

ND

ES

BIO

SC

IEN

CE

Macrophage migration inhibitory factor MIF is a ubiquitously expressed, predominantly cytoplasmic protein that has been implicated in the regulation of cell growth and development.21 In addition, MIF has been recognized as a critical component of the immune system that regulates the pro‑inflammatory properties of immune cells.22,23 The growth regulatory nature of MIF’s activities first became apparent when it was shown to be regulated by differentiation of fibroblasts in eye lenses.24 A few years later, elaborate genetic screens surprisingly identified MIF as a functional p53 antagonist.25 Strikingly, although MIF did not bind to p53 directly, it still reduced the transcriptional activity of p53. Moreover, MIF is frequently overexpressed in human tumors and was reported to possess tumor‑promoting activity.26‑37 Importantly, these initial observations were confirmed by gene knockout studies that clearly demonstrated that MIF mediates many of its growth‑ and tumor‑promoting effects via p53‑dependent mechanisms.38‑40 Although a number of cell cycle‑associated proteins such as Rb, E2Fs, p16, p21 and p27 were also found altered in MIF deficiency, the underlying mechanism of MIF activity remained elusive at first. Subsequently, a search for intracellular MIF‑binding partners by the yeast two‑hybrid system yielded Jab1/CSN5 as potential candidate.41 Soon thereafter, it was shown that intracellular MIF indeed binds to the metalloprotease MPN domain of Jab1 and that MIF inhibits Jab1 function by preventing it from interacting with other cellular proteins.42 Our own recent study showed that this regulation of Jab1 by MIF is a physiologic requirement to sustain optimal composition and activity of SCF ubiquitin ligases, which are known to play a pivotal role in the regulation of cellular responses to DNA damage.43

www.landesbioscience.com

Implications for MIF’s Role in Tumor Development: A Question of Context Clearly, this novel prospect of MIF as a coordinator between DNA damage response and proteasomal control of the cell cycle necessitates a more facetted view of MIF’s role in tumorigenesis. Previous animal‑based studies showed that MIF acts to promote cell survival and tumor formation. Moreover, these MIF effects were mediated by inhibiting p53 function.38,40 Hence, MIF was classified as a tumor promoter 45 and a potential oncogene.46 However, several other observations did not support this view: (1) While increased MIF expression in various human cancers was

Cell Cycle

1031


OT D

IST RIB

UT E

.

breaks is linked with the formation of aberrant translocations, creating conditions for Myc amplification and the development of pro‑B‑cell lymphomas.52,53 Consistent with this, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) revealed that MIF‑deficient B‑cell lymphomas harbor clonal gene amplifications and chromosomal translocations that are reported in mice with dual impairment of p53 and DNA double‑strand break repair or non-homologous end joining,52,54‑57 suggesting a potential role for MIF in the maintenance of genomic stability (Fig. 2). Likewise, both elevated Cdc25A and Cdk2 are frequently associated with the development of human carcinomas.44,58 In sum, our data indicate that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 specifically antagonize each other in the cell. While the loss of MIF expression induces a p53‑dependent proliferative block,38,40 concomitant loss of p53 rescues these growth defects, but it comes at the price of increased tumorigenesis.

Is MIF a Valid Target for Anti‑Cancer Strategies?

Figure 1. Macrophage migration inhibitory factor controls SCF activity via Jab1. The SCF E3 ubiquitin ligase consists of Cullins, Skp1 and F‑box proteins which associate to form an enzymatically active complex. The posttranslational modification of Cullin (Cul1) by Nedd8 (presumably via involvement of Rbx1) renders SCF active, though unstable. The removal of Nedd8 (deneddylation) from Cullin is catalyzed by the jun‑activating bind‑ ing protein‑1 (Jab1), also known as subunit 5 of the COP9/CSN signalosome (CSN5). Following deneddylation of Cullins, Skp1 and F‑box proteins are replaced by the inhibi‑ tory protein Cand‑1. MIF binds to the MPN domain of Jab1 and prevents it from interact‑ ing with proteins targeted by CSN, notably the Cullins.

IEN

CE

.D

ON

Since most tumor cells harbor a disabled G1 checkpoint due to mutations of p53‑ and Rb‑related pathways, they largely rely on a functional G2M checkpoint. The G2M checkpoint elicits signals that not only trigger growth arrest or apoptosis, but also direct activation of DNA repair networks. Therefore, severe disabling of G2M signaling is viewed as a possible novel anticancer strategy.5,58 It is conceivable that the combination of chemotherapy with additional inactivation of G2M checkpoint function would favor tumor cell death by enhancing the cytotoxic effect of chemotherapeutic reagents and drive cancer cells into mitotic catastrophe.59 Evidence supporting a role of MIF in CSN function and in the G2M checkpoint response indicates that it could be an attractive target for therapeutic intervention. Disabling SCF activity directly, at the same time when the G2M checkpoint is engaged by genotoxic drugs, holds promise to effectively attack cancer cells. Importantly, this strategy would do relatively little damage to normal cells, since they would still be able to activate their G1 checkpoint, safeguarded by the p53 and Rb tumor suppressors. Specifically, targeting the MIF‑Jab1‑SCF interaction may have broad implications, since deregulated SCF plays a fundamental role in the development and survival of many types of human malignancies.11 The clinical success of Bortezomib, a small molecule that inhibits the active site of the proteasome in the treatment of lymphoid malignancies60 has stimulated excitement in exploring other modulators of the UPS system. Unspecific proteasome inhibitors like Bortezomib present the cell with contradictory signals and this conflict triggers apoptosis. Since Bortezomib blocks the entire proteasomal degradation system, it has a narrow therapeutic window and requires careful monitoring of the patient to avoid fatal toxicity. Yet, while the broad, unspecific action of Bortezomib limits its clinical usefulness, it also stimulates the search for other targets within the same pathway but with higher specificity. The emerging molecular complexity of the SCF, with substrate specificity mediated via different F‑box proteins

©

20

07

LA

ND

ES

BIO

SC

reported,28,32,37,47-49 and in some cases correlated with poor prognosis,32,37,49 two reports indicated that aberrantly low levels of MIF in human tumors correlated with poor clinical outcome.50,51 (2) Chemical one stage‑ and two stage‑skin carcinogenesis experiments showed that MIF‑deficiency leads to an increased rate of tumor formation in C57Bl/6 and 129Sv mice (Fingerle‑Rowson G, unpublished). These results are inconsistent with the view of MIF as a tumor promoter in murine skin. (3) Our recent experiments using MIF‑knockout mice on a p53‑null background showed that MIF deficiency leads to a remarkable shift in tumor spectrum: while the expected high frequency of T‑cell lymphomas and fibrosarcomas was reduced upon MIF deficiency, the frequency of B‑cell lymphomas and carcinomas (very unusual in a p53‑null background) was strongly increased. Moreover, the shift in tumor spectrum led to significantly decreased survival of MIF‑/‑p53‑/‑ mice compared to p53‑/‑ controls.43 Given that MIF plays a key role in the regulation of SCF, and hence of the abundance and activity of Cdk2/cyclin A and E2F1/DP1 complexes which both can induce a strong p53‑dependent antiproliferative response, our data suggested that the involvement of MIF in p53 function is secondary to p53‑independent mechanisms controlling protein stability, checkpoint regulation and the integrity of the genome. Moreover, we showed that the tumor phenotype of MIF‑/‑p53‑/‑ mice entails defects in the checkpoint response and DNA repair process. Thus, failure to cease proliferation of p53‑deficient cells with DNA double‑strand 1032

Cell Cycle



IEN

CE

.D

ON

OT D

IST RIB

UT E

.

8. Yamasaki L, Pagano M. Cell cycle, proteolysis and cancer. Curr Opin Cell Biol 2004; 16:623‑8. 9. Ciechanover A. The ubiquitin‑proteasome pathway: On protein death and cell life. Embo J 1998; 17:7151‑60. 10. Donzelli M, Draetta GF. Regulating mammalian checkpoints through Cdc25 inactivation. EMBO Rep 2003; 4:671‑7. 11. Nakayama KI, Nakayama K. Ubiquitin ligases: Cell‑cycle control and cancer. Nat Rev Cancer 2006; 6:369‑81. 12. Cardozo T, Pagano M. The SCF ubiquitin ligase: Insights into a molecular machine. Nat Rev Mol Cell Biol 2004; 5:739‑51. 13. Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW. Systematic analysis and nomenclature of mammalian F‑box proteins. Genes Dev 2004; 18:2573‑80. 14. Bornstein G, Ganoth D, Hershko A. Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F‑box protein and substrate. Proc Natl Acad Sci USA 2006; 103:11515‑20. 15. Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Deshaies RJ. Promotion of NEDD‑CUL1 conjugate cleavage by COP9 signalosome. Science 2001; 292:1382‑5. 16. Cope GA, Suh GS, Aravind L, Schwarz SE, Zipursky SL, Koonin EV, Deshaies RJ. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science 2002; 298:608‑11. 17. Zhou C, Wee S, Rhee E, Naumann M, Dubiel W, Wolf DA. Fission yeast COP9/signalosome suppresses cullin activity through recruitment of the deubiquitylating enzyme Ubp12p. Mol Cell 2003; 11:927‑38. 18. Liu J, Furukawa M, Matsumoto T, Xiong Y. NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1‑SKP1 binding and SCF ligases. Mol Cell 2002; 10:1511‑8. 19. Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke‑Andersen K, Wei N, Sun H, Kobayashi R, Zhang H. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol Cell 2002; 10:1519‑26. 20. Petroski MD, Deshaies RJ. Function and regulation of cullin‑RING ubiquitin ligases. Nat Rev Mol Cell Biol 2005; 6:9‑20. 21. Mitchell R. Mechanisms and effectors of MIF‑dependent promotion of tumourigenesis. Cellular Signalling 2004; 16:13‑9. 22. Baugh JA, Bucala R. Macrophage migration inhibitory factor. Crit Care Med 2002; 30: S27‑S35. 23. Calandra T, Roger T. Macrophage migration inhibitory factor: A regulator of innate immunity. Nat Rev Immunol 2003; 3:791‑800. 24. Wistow GJ, Shaughnessy MP, Lee DC, Hodin J, Zelenka PS. A macrophage migration inhibitory factor is expressed in the differentiating cells of the eye lens. Proc Natl Acad Sci USA 1993; 90:1272‑5. 25. Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH. A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med 1999; 190:1375‑82. 26. Meyer‑Siegler KL, Iczkowski KA, Leng L, Bucala R, Vera PL. Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU‑145 prostate cancer cells. J Immunol 2006; 177:8730‑9. 27. Takahashi H, Nemoto T, Yoshida T, Honda H, Hasegawa T. Cancer diagnosis marker extraction for soft tissue sarcomas based on gene expression profiling data by using projective adaptive resonance theory (PART) filtering method. BMC Bioinformatics 2006; 7:399. 28. He XX, Yang J, Ding YW, Liu W, Shen QY, Xia HH. Increased epithelial and serum expression of macrophage migration inhibitory factor (MIF) in gastric cancer: Potential role of MIF in gastric carcinogenesis. Gut 2006; 55:797‑802. 29. Ren Y, Chan HM, Fan J, Xie Y, Chen YX, Li W, Jiang GP, Liu Q, Meinhardt A, Tam PK. Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma. Oncogene 2006; 25:3501‑8. 30. Miracco C, De Nisi MC, Arcuri F, Cosci E, Pacenti L, Toscano M, Lalinga AV, Biagioli M, Rubegni P, Vatti R, Maellaro E, Del Bello B, Massi D, Luzi P, Tosi P. Macrophage migration inhibitory factor protein and mRNA expression in cutaneous melanocytic tumours. Int J Oncol 2006; 28:345‑52. 31. Wilson JM, Coletta PL, Cuthbert RJ, Scott N, MacLennan K, Hawcroft G, Leng L, Lubetsky JB, Jin KK, Lolis E, Medina F, Brieva JA, Poulsom R, Markham AF, Bucala R, Hull MA. Macrophage migration inhibitory factor promotes intestinal tumorigenesis. Gastroenterology 2005; 129:1485‑503. 32. Ren Y, Law S, Huang X, Lee PY, Bacher M, Srivastava G, Wong J. Macrophage migration inhibitory factor stimulates angiogenic factor expression and correlates with differentiation and lymph node status in patients with esophageal squamous cell carcinoma. Ann Surg 2005; 242:55‑63. 33. Shun CT, Lin JT, Huang SP, Lin MT, Wu MS. Expression of macrophage migration inhibitory factor is associated with enhanced angiogenesis and advanced stage in gastric carcinomas. World J Gastroenterol 2005; 11:3767‑71. 34. Sun B, Nishihira J, Yoshiki T, Kondo M, Sato Y, Sasaki F, Todo S. Macrophage migration inhibitory factor promotes tumor invasion and metastasis via the Rho‑dependent pathway. Clin Cancer Res 2005; 11:1050‑8. 35. Nishihira J, Ishibashi T, Fukushima T, Sun B, Sato Y, Todo S. Macrophage migration inhibitory factor (MIF): Its potential role in tumor growth and tumor‑associated angiogenesis. Ann N Y Acad Sci 2003; 995:171‑82.

LA

ND

ES

BIO

SC

Figure 2. Chromosomal aberrations in MIF/p53 deficient B‑cell lymphomas. (A and B) Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses of representative MIF/p53 deficient B‑cell tumors carrying reciprocal translocation t(12;15) that juxtaposes the c‑Myc gene to antigen receptor loci (A) or non-reciprocal translocation t(12; 16) carrying amplified N‑Myc gene (B, green) at the fusion of chromosomes 12 and 16. Other translocations revealed by SKY harbored portions of chromosomes 3, 6, 7, 13, 15, and 17 (A, B). Similar cytogenetic alterations are characteristic of mice with dual impairment of p53 and DNA double‑strand break repair or non-homologous end joining.55‑57

07

and additional regulatory modulators such as MIF, is likely to yield ample opportunities to develop improved and novel therapeutic strategies for cancer treatment.

20

References

©

1. Rich T, Allen RL, Wyllie AH. �� Defying death after DNA damage. Nature 2000; 407:777‑83. 2. Nyberg KA, Michelson RJ, Putnam CW, Weinert TA. Toward maintaining the genome: DNA damage and replication checkpoints. Annu Rev Genet 2002; 36:617‑56. 3. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002; 2:103‑12. 4. Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 2003; 3:421‑9. 5. Bartek J, Lukas C, Lukas J. Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 2004; 5:792‑804. 6. Malumbres M, Barbacid M. Cell cycle kinases in cancer. �� Curr Opin Genet Dev 2007; 17:60‑5. 7. Bloom J, Cross FR. �� Multiple levels of cyclin specificity in cell‑cycle control. Nat Rev Mol Cell Biol 2007; 8:149‑60.

www.landesbioscience.com

Cell Cycle

1033

UT E IST RIB OT D

©

20

07

LA

ND

ES

BIO

SC

IEN

CE

.D

ON

36. Meyer‑Siegler KL, Leifheit EC, Vera PL. Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells. BMC Cancer 2004; 4:34. 37. Kamimura A, Kamachi M, Nishihira J, Ogura S, Isobe H, Dosaka‑Akita H, Ogata A, Shindoh M, Ohbuchi T, Kawakami Y. Intracellular distribution of macrophage migration inhibitory factor predicts the prognosis of patients with adenocarcinoma of the lung. Cancer 2000; 89:334‑41. 38. Fingerle‑Rowson G, Petrenko O, Metz CN, Forsthuber TG, Mitchell R, Huss R, Moll U, Muller W, Bucala R. The p53‑dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci USA 2003; 100:9354‑9. 39. Petrenko O, Fingerle‑Rowson G, Peng T, Mitchell RA, Metz CN. Macrophage migration inhibitory factor deficiency is associated with altered cell growth and reduced susceptibility to Ras‑mediated transformation. J Biol Chem 2003; 278:11078‑85. 40. Talos F, Mena P, Fingerle‑Rowson G, Moll U, Petrenko O. MIF loss impairs Myc‑induced lymphomagenesis. Cell Death Differ 2005; 12:1319‑28. 41. Kleemann R, Hausser A, Geiger G, Mischke R, Burger‑Kentischer A, Flieger O, Johannes FJ, Roger T, Calandra T, Kapurniotu A, Grell M, Finkelmeier D, Brunner H, Bernhagen J. Intracellular action of the cytokine MIF to modulate AP‑1 activity and the cell cycle through Jab1. Nature 2000; 408:211‑6. 42. Burger‑Kentischer A, Finkelmeier D, Thiele M, Schmucker J, Geiger G, Tovar GE, Bernhagen J. Binding of JAB1/CSN5 to MIF is mediated by the MPN domain but is independent of the JAMM motif. FEBS Lett 2005; 579:1693‑701. 43. Nemajerova A, Mena P, Fingerle‑Rowson G, Moll UM, Petrenko O. Impaired DNA damage checkpoint response in MIF‑deficient mice. Embo J 2007; 26:987‑97. 44. Busino L, Chiesa M, Draetta GF, Donzelli M. Cdc25A phosphatase: Combinatorial phosphorylation, ubiquitylation and proteolysis. Oncogene 2004; 23:2050‑6. 45. Mitchell RA, Bucala R. Tumor growth‑promoting properties of macrophage migration inhibitory factor (MIF). Semin Cancer Biol 2000; 10:359‑66. 46. Ren Y, Chan HM, Li Z, Lin C, Nicholls J, Chen CF, Lee PY, Lui V, Bacher M, Tam PK. Upregulation of macrophage migration inhibitory factor contributes to induced N‑Myc expression by the activation of ERK signaling pathway and increased expression of interleukin‑8 and VEGF in neuroblastoma. Oncogene 2004; 23:4146‑54. 47. Meyer‑Siegler K. Increased stability of macrophage migration inhibitory factor (MIF) in DU‑145 prostate cancer cells. J Interferon Cytokine Res 2000; 20:769‑78. 48. Meyer‑Siegler K, Hudson PB. Enhanced expression of macrophage migration inhibitory factor in prostatic adenocarcinoma metastases. Urology 1996; 48:448‑52. 49. Tomiyasu M, Yoshino I, Suemitsu R, Okamoto T, Sugimachi K. Quantification of macrophage migration inhibitory factor mRNA expression in non-small cell lung cancer tissues and its clinical significance. Clin Cancer Res 2002; 8:3755‑60. 50. del Vecchio MT, Tripodi SA, Arcuri F, Pergola L, Hako L, Vatti R, Cintorino M. Macrophage migration inhibitory factor in prostatic adenocarcinoma: Correlation with tumor grading and combination endocrine treatment‑ related changes. Prostate 2000; 45:51‑7. 51. Suzuki F, Nakamaru Y, Oridate N, Homma A, Nagahashi T, Yamaguchi S, Nishihira J, Furuta Y, Fukuda S. Prognostic significance of cytoplasmic macrophage migration inhibitory factor expression in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy. Oncol Rep 2005; 13:59‑64. 52. Maser RS, DePinho RA. Take care of your chromosomes lest cancer take care of you. Cancer Cell 2003; 3:4‑6. 53. Kuppers R. Mechanisms of B‑cell lymphoma pathogenesis. Nat Rev Cancer 2005; 5:251‑62. 54. Bassing CH, Alt FW. The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst) 2004; 3:781‑96. 55. Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, Ried T, Nussenzweig A. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 2000; 404:510‑4. 56. Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C, Manis JP, Horner J, DePinho RA, Alt FW. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 2000; 5:993‑1002. 57. Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW. Interplay of p53 and DNA‑repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 2000; 404:897‑900. 58. Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: Aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005; 5:773‑85. 59. Mansilla S, Bataller M, Portugal J. Mitotic catastrophe as a consequence of chemotherapy. Anticancer Agents Med Chem 2006; 6:589‑602. 60. Richardson PG, Mitsiades C, Hideshima T, Anderson KC. Bortezomib: Proteasome inhibition as an effective anticancer therapy. Annu Rev Med 2006; 57:33‑47.

.


1034

Cell Cycle
