Tumor Suppressor Protein C53 Antagonizes Checkpoint Kinases to Promote Cyclin-dependent Kinase 1 Activation

Overview

Journal Cell Res

Specialty Cell Biology

Date 2009 Feb 19

PMID 19223857

Citations 32

Authors

Hai Jiang

Jianchun Wu

Chen He

Wending Yang

Honglin Li

Affiliations

Soon will be listed here.

Abstract

Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. (2007) found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-kappaB signaling. We report here the identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexpression. Intriguingly, we found that C53 interacts with Chk1 and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.

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References

Wang J, He X, Luo Y, Yarbrough W . A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2. Biochem J. 2005; 393(Pt 2):489-501. PMC: 1360699. DOI: 10.1042/BJ20050960. View

Jackman M, Lindon C, Nigg E, Pines J . Active cyclin B1-Cdk1 first appears on centrosomes in prophase. Nat Cell Biol. 2003; 5(2):143-8. DOI: 10.1038/ncb918. View

Dozier C, Bonyadi M, Baricault L, Tonasso L, Darbon J . Regulation of Chk2 phosphorylation by interaction with protein phosphatase 2A via its B' regulatory subunit. Biol Cell. 2004; 96(7):509-17. DOI: 10.1016/j.biolcel.2004.04.010. View

Ward I, Chen J . Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem. 2001; 276(51):47759-62. DOI: 10.1074/jbc.C100569200. View

Tsvetkov L, Xu X, Li J, Stern D . Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody. J Biol Chem. 2002; 278(10):8468-75. DOI: 10.1074/jbc.M211202200. View

Shiloh Y . Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet. 1997; 31:635-62. DOI: 10.1146/annurev.genet.31.1.635. View

Sancar A, Lindsey-Boltz L, Unsal-Kacmaz K, Linn S . Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem. 2004; 73:39-85. DOI: 10.1146/annurev.biochem.73.011303.073723. View

Jiang H, Luo S, Li H . Cdk5 activator-binding protein C53 regulates apoptosis induced by genotoxic stress via modulating the G2/M DNA damage checkpoint. J Biol Chem. 2005; 280(21):20651-9. DOI: 10.1074/jbc.M413431200. View

Brown E, Baltimore D . ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 2000; 14(4):397-402. PMC: 316378. View

10.

Cimprich K, Shin T, Keith C, Schreiber S . cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. Proc Natl Acad Sci U S A. 1996; 93(7):2850-5. PMC: 39722. DOI: 10.1073/pnas.93.7.2850. View

11.

Li H, Bergeron L, Cryns V, Pasternack M, Zhu H, Shi L . Activation of caspase-2 in apoptosis. J Biol Chem. 1997; 272(34):21010-7. DOI: 10.1074/jbc.272.34.21010. View

12.

Oliva-Trastoy M, Berthonaud V, Chevalier A, Ducrot C, Marsolier-Kergoat M, Mann C . The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase. Oncogene. 2006; 26(10):1449-58. DOI: 10.1038/sj.onc.1209927. View

13.

Liu Q, Guntuku S, Cui X, Matsuoka S, Cortez D, Tamai K . Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000; 14(12):1448-59. PMC: 316686. View

14.

Ching Y, Qi Z, Wang J . Cloning of three novel neuronal Cdk5 activator binding proteins. Gene. 2000; 242(1-2):285-94. DOI: 10.1016/s0378-1119(99)00499-0. View

15.

Wang J, An H, Mayo M, Baldwin A, Yarbrough W . LZAP, a putative tumor suppressor, selectively inhibits NF-kappaB. Cancer Cell. 2007; 12(3):239-51. DOI: 10.1016/j.ccr.2007.07.002. View

16.

Ng C, Lee H, Ho C, Arooz T, Siu W, Lau A . Differential mode of regulation of the checkpoint kinases CHK1 and CHK2 by their regulatory domains. J Biol Chem. 2003; 279(10):8808-19. DOI: 10.1074/jbc.M312215200. View

17.

Kramer A, Lukas J, Bartek J . Checking out the centrosome. Cell Cycle. 2004; 3(11):1390-3. DOI: 10.4161/cc.3.11.1252. View

18.

Matsuoka S, Huang M, Elledge S . Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998; 282(5395):1893-7. DOI: 10.1126/science.282.5395.1893. View

19.

Kramer A, Mailand N, Lukas C, Syljuasen R, Wilkinson C, Nigg E . Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Nat Cell Biol. 2004; 6(9):884-91. DOI: 10.1038/ncb1165. View

20.

Zhou B, Bartek J . Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer. 2004; 4(3):216-25. DOI: 10.1038/nrc1296. View