cdc2 cdc28 kinases


Summary: A family of cell cycle-dependent kinases that are related in structure to CDC28 PROTEIN KINASE; S CEREVISIAE; and the CDC2 PROTEIN KINASE found in mammalian species.

Top Publications

  1. Diederichs S, Baumer N, Ji P, Metzelder S, Idos G, Cauvet T, et al. Identification of interaction partners and substrates of the cyclin A1-CDK2 complex. J Biol Chem. 2004;279:33727-41 pubmed
    ..Thereby, we establish a new basis for future functional analyses of cyclin A1. We provide evidence that the cyclin A1-CDK2 complex plays a role in several signaling pathways important for cell cycle control and meiosis. ..
  2. Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet. 2003;35:25-31 pubmed
    ..But CDK2 is essential for completion of prophase I during meiotic cell division in male and female germ cells, an unforeseen role for this cell cycle kinase. ..
  3. Henneke G, Koundrioukoff S, Hubscher U. Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation. Oncogene. 2003;22:4301-13 pubmed
    ..Our results suggest a novel regulatory role of Cdks onto the end of S phase by targeting directly a key enzyme involved in DNA replication. ..
  4. Nakayama K, Nagahama H, Minamishima Y, Miyake S, Ishida N, Hatakeyama S, et al. Skp2-mediated degradation of p27 regulates progression into mitosis. Dev Cell. 2004;6:661-72 pubmed
    ..These data suggest that p27 proteolysis is necessary for the activation of not only Cdk2 but also Cdc2, and that Skp2 contributes to regulation of G(2)-M progression by mediating the degradation of p27. ..
  5. McAllister S, Becker Hapak M, Pintucci G, Pagano M, Dowdy S. Novel p27(kip1) C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. Mol Cell Biol. 2003;23:216-28 pubmed
    ..These observations define a novel role for p27 in cell motility that is independent of its function in cell cycle inhibition. ..
  6. Bashir T, Dorrello N, Amador V, Guardavaccaro D, Pagano M. Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature. 2004;428:190-3 pubmed
    ..Thus, the induction of Skp2 and Cks1 degradation in G1 represents a principal mechanism by which APC/C(Cdh1) prevents the unscheduled degradation of SCF(Skp2-Cks1) substrates and maintains the G1 state. ..
  7. Aleem E, Berthet C, Kaldis P. Cdk2 as a master of S phase entry: fact or fake?. Cell Cycle. 2004;3:35-7 pubmed
  8. Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P. Cdk2 knockout mice are viable. Curr Biol. 2003;13:1775-85 pubmed
    ..Loss of Cdk2 affects the timing of S phase, suggesting that Cdk2 is involved in regulating progression through the mitotic cell cycle. ..
  9. Tetsu O, McCormick F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell. 2003;3:233-45 pubmed
    ..Here we report of sustained cell proliferation in the absence of CDK2, and we suggest that CDK2 is not a suitable target for cancer therapy. ..

More Information


  1. Muller Tidow C, Ji P, Diederichs S, Potratz J, Baumer N, Kohler G, et al. The cyclin A1-CDK2 complex regulates DNA double-strand break repair. Mol Cell Biol. 2004;24:8917-28 pubmed
    ..DNA DSB repair was specific for A-type cyclins because cyclin E was ineffective. These findings establish a novel function for cyclin A1 and CDK2 in DNA DSB repair following radiation damage. ..
  2. Coulombe P, Rodier G, Pelletier S, Pellerin J, Meloche S. Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation. Mol Cell Biol. 2003;23:4542-58 pubmed
    ..Interestingly, we found that expression of stabilized forms of ERK3 causes G(1) arrest in NIH 3T3 cells. We propose that ERK3 biological activity is regulated by its cellular abundance through the control of protein stability. ..
  3. Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor M, Han K, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002;8:1153-60 pubmed
    ..Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer. ..
  4. Law B, Chytil A, Dumont N, Hamilton E, Waltner Law M, Aakre M, et al. Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol Cell Biol. 2002;22:8184-98 pubmed
    ..Together, these results indicate that rapamycin and TGF-beta cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity. ..
  5. Shin I, Yakes F, Rojo F, Shin N, Bakin A, Baselga J, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002;8:1145-52 pubmed
    ..These data indicate that Akt may contribute to tumor-cell proliferation by phosphorylation and cytosolic retention of p27, thus relieving CDK2 from p27-induced inhibition. ..
  6. Tedesco D, Lukas J, Reed S. The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2). Genes Dev. 2002;16:2946-57 pubmed
    ..Thus, like the Cdk inhibitor p27(Kip1), p130 turnover is regulated by Cdk-dependent G1 phosphorylation leading to ubiquitin-dependent proteolysis. ..
  7. Wu G, Vieth M. SDOCKER: a method utilizing existing X-ray structures to improve docking accuracy. J Med Chem. 2004;47:3142-8 pubmed
    ..The strategy of utilizing existing ligand X-ray information should prove effective in light of the multitude of structures available from structural genomics approaches. ..
  8. Offman M, Nurtdinov R, Gelfand M, Frishman D. No statistical support for correlation between the positions of protein interaction sites and alternatively spliced regions. BMC Bioinformatics. 2004;5:41 pubmed
    ..More structural data on complexes of interacting proteins, including structures of alternative isoforms, are needed to test this conjecture. ..
  9. Knight Krajewski S, Welsh C, Liu Y, Lyons L, Faysal J, Yang E, et al. Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21(CIP1) levels in androgen-independent human prostate cancer cells. Oncogene. 2004;23:5513-22 pubmed
  10. Chuaqui C, Deng Z, Singh J. Interaction profiles of protein kinase-inhibitor complexes and their application to virtual screening. J Med Chem. 2005;48:121-33 pubmed
    ..Interaction-based analysis should provide a valuable tool for understanding inhibitor binding to other important drug targets. ..
  11. Wood E, Kuyper L, Petrov K, Hunter R, Harris P, Lackey K. Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorg Med Chem Lett. 2004;14:953-7 pubmed
  12. Chen X, Oh S, Zheng Z, Chen H, Shin H, Hou S. Cyclin D-Cdk4 and cyclin E-Cdk2 regulate the Jak/STAT signal transduction pathway in Drosophila. Dev Cell. 2003;4:179-90 pubmed
    ..STAT92E regulates gene expression for various biological processes, including the endocycle S phase. These data suggest that Cyclin D-Cdk4 and Cyclin E-Cdk2 play more versatile roles in Drosophila development. ..
  13. Granes F, Roig M, Brady H, Gil Gomez G. Cdk2 activation acts upstream of the mitochondrion during glucocorticoid induced thymocyte apoptosis. Eur J Immunol. 2004;34:2781-90 pubmed
    ..Our data allow an integrated linear pathway regulating DNA damage and glucocorticoid-induced thymocyte apoptosis to be proposed. ..
  14. Chun K, Kim D, Nam Y, Lee S. PEP8-TAT2, a membrane-permeable peptide, inhibits cyclin-Cdk2 activity in HeLa cells. Cancer Lett. 2004;213:223-30 pubmed
    ..We propose that this inhibitor peptide is an effective agent to suppress the proliferation of human cancer cells, as well as apoptotic progression, by blocking cellular cyclin-dependent Cdk kinase activity. ..
  15. Akli S, Zheng P, Multani A, Wingate H, Pathak S, Zhang N, et al. Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. Cancer Res. 2004;64:3198-208 pubmed
  16. Zhang H, McElrath T, Tong W, Pollard J. The molecular basis of tamoxifen induction of mouse uterine epithelial cell proliferation. J Endocrinol. 2005;184:129-40 pubmed
  17. Honda R, Lowe E, Dubinina E, Skamnaki V, Cook A, Brown N, et al. The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2-independent roles. EMBO J. 2005;24:452-63 pubmed
    ..The structural and kinetic results indicate no inherent substrate discrimination between pCDK2/cyclin E and pCDK2/cyclin A with model substrates. ..
  18. Li X, Huang P, Cui J, Zhang J, Tang C. Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors. Bioorg Med Chem Lett. 2003;13:1939-42 pubmed
  19. Bae M, Rhee H, Song B. Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines. Toxicol Lett. 2003;139:67-75 pubmed
    ..Furthermore, because RSG did not affect the levels of cell cycle regulators, TRO-mediated growth inhibition appears independent of PPARgamma activation. ..
  20. Ducruet A, Lazo J. Regulation of Cdc25A half-life in interphase by cyclin-dependent kinase 2 activity. J Biol Chem. 2003;278:31838-42 pubmed
    ..These results demonstrate Cdk2 kinase activity contributes to the labile nature of Cdc25A during interphase and redefine the nature of the Cdc25A-Cdk2 autoamplification feedback loop. ..
  21. Bhat R, Xue Y, Berg S, Hellberg S, Ormö M, Nilsson Y, et al. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J Biol Chem. 2003;278:45937-45 pubmed
    ..AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5. ..
  22. Uttamsingh S, Zong C, Wang L. Matrix-independent activation of phosphatidylinositol 3-kinase, Stat3, and cyclin A-associated Cdk2 Is essential for anchorage-independent growth of v-Ros-transformed chicken embryo fibroblasts. J Biol Chem. 2003;278:18798-810 pubmed
  23. Groth A, Willumsen B. High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27(Kip) Cdk-complexes. Cell Signal. 2005;17:1063-73 pubmed
    ..This demonstrates that although oncogenic Ras efficiently disabled the normal response to contact inhibition, a separate back-up mechanism enforced cell cycle arrest at higher cell density. ..
  24. Lolli G, Thaler F, Valsasina B, Roletto F, Knapp S, Uggeri M, et al. Inhibitor affinity chromatography: profiling the specific reactivity of the proteome with immobilized molecules. Proteomics. 2003;3:1287-98 pubmed
    ..These results support the use of IAC as a general method for the rapid identification and qualitative evaluation of the in vivo targets and potential side effects of a given drug. ..
  25. Li J, Wu F, Usuki H, Kubo A, Masaki T, Fujita J, et al. Loss of p57KIP2 is associated with colorectal carcinogenesis. Int J Oncol. 2003;23:1537-43 pubmed
    ..0007), elevated cyclin B1 (p=0.0007), reduced CDK2 (p=0.0021), and increased Ki67 (p=0.0013) in adenomas. Thus, loss of p57KIP2 expression appears associated with colorectal carcinogenesis. ..
  26. Pevarello P, Brasca M, Amici R, Orsini P, Traquandi G, Corti L, et al. 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding. J Med Chem. 2004;47:3367-80 pubmed
  27. Kavurma M, Khachigian L. Sp1 inhibits proliferation and induces apoptosis in vascular smooth muscle cells by repressing p21WAF1/Cip1 transcription and cyclin D1-Cdk4-p21WAF1/Cip1 complex formation. J Biol Chem. 2003;278:32537-43 pubmed
    ..These findings, using complementary approaches, demonstrate the inverse relationship between Sp1 and p21WAF1/Cip1 in SMCs and the capacity of Sp1 to regulate SMC proliferation and apoptosis via its repression of p21WAF1/Cip1. ..
  28. Cifuentes E, Croxen R, Menon M, Barrack E, Reddy G. Synchronized prostate cancer cells for studying androgen regulated events in cell cycle progression from G1 into S phase. J Cell Physiol. 2003;195:337-45 pubmed
  29. Ji P, Jiang H, Rekhtman K, Bloom J, Ichetovkin M, Pagano M, et al. An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol Cell. 2004;16:47-58 pubmed
    ..These results identify an Rb-Skp2-p27 pathway in Rb function, which may be involved in inhibition of tumor progression. ..
  30. Arakaki N, Toyofuku A, Emoto Y, Nagao T, Kuramoto Y, Shibata H, et al. Induction of G1 cell cycle arrest in human umbilical vein endothelial cells by flavone's inhibition of the extracellular signal regulated kinase cascade. Biochem Cell Biol. 2004;82:583-8 pubmed
  31. Takeo K, Ogura Y, Virtudazo E, Raclavsky V, Kawamoto S. Isolation of a CDC28 homologue from Cryptococcus neoformans that is able to complement cdc28 temperature-sensitive mutants of Saccharomyces cerevisiae. FEMS Yeast Res. 2004;4:737-44 pubmed
    ..Results of the sequence analysis and the fact that CnCdk1 is able to complement the S. cerevisiae cdc28-ts mutation support its assumed role as the CDC28/cdc2 homologue in C. neoformans. ..
  32. Eguchi H, Herschenhous N, Kuzushita N, Moss S. Helicobacter pylori increases proteasome-mediated degradation of p27(kip1) in gastric epithelial cells. Cancer Res. 2003;63:4739-46 pubmed
    ..Increased degradation of p27 by H. pylori through a proteasome-dependent, ubiquitin-independent pathway may contribute to the increased risk of gastric cancer associated with chronic H. pylori infection. ..
  33. Dormond O, Lejeune F, Ruegg C. Modulation of cdk2, cyclin D1, p16INK4a, p21WAF and p27Kip1 expression in endothelial cells by TNF/IFN gamma. Anticancer Res. 2002;22:3159-63 pubmed
  34. Anderson M, Beattie J, Breault G, Breed J, Byth K, Culshaw J, et al. Imidazo[1,2-a]pyridines: a potent and selective class of cyclin-dependent kinase inhibitors identified through structure-based hybridisation. Bioorg Med Chem Lett. 2003;13:3021-6 pubmed
    ..Comparison of their experimentally-determined binding modes and emerging structure-activity trends led to the development of potent and selective imidazo[1,2-a]pyridine inhibitors for CDK4 and in particular CDK2. ..
  35. Chinami M, Yano Y, Yang X, Salahuddin S, Moriyama K, Shiroishi M, et al. Binding of HTm4 to cyclin-dependent kinase (Cdk)-associated phosphatase (KAP).Cdk2.cyclin A complex enhances the phosphatase activity of KAP, dissociates cyclin A, and facilitates KAP dephosphorylation of Cdk2. J Biol Chem. 2005;280:17235-42 pubmed
    ..We show that this interaction not only facilitates access of KAP to Thr160 and accelerates KAP kinetics, but also forces exclusion of cyclin A from the KAP.cdk2 complex. ..
  36. Charles M, Adamski D, Kholler B, Pelletier L, Berger F, Wion D. Induction of neurite outgrowth in PC12 cells by the bacterial nucleoside N6-methyldeoxyadenosine is mediated through adenosine A2a receptors and via cAMP and MAPK signaling pathways. Biochem Biophys Res Commun. 2003;304:795-800 pubmed
    ..Collectively, these findings suggest that, in PC12 cells, the MDA-induced neuritogenesis requires the recruitment of adenosine A(2a) receptor, the stimulation of adenylate cyclase, and the activation of the p44/42MAP kinase cascade. ..
  37. Gondeau C, Gerbal Chaloin S, Bello P, Aldrian Herrada G, Morris M, Divita G. Design of a novel class of peptide inhibitors of cyclin-dependent kinase/cyclin activation. J Biol Chem. 2005;280:13793-800 pubmed
    ..Moreover, when coupled with the protein transduction domain of Tat, the C4 peptide blocks the proliferation of tumor cell lines, thereby constituting a potent lead for the development of specific CDK-cyclin inhibitors. ..
  38. Schellhammer I, Rarey M. FlexX-Scan: fast, structure-based virtual screening. Proteins. 2004;57:504-17 pubmed
    ..With FlexX-Scan, we achieved comparable enrichments to standard FlexX, with an averaged computing time of 5-10 s per compound, depending on parametrization. ..
  39. Heath E, Bible K, Martell R, Adelman D, LoRusso P. A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors. Invest New Drugs. 2008;26:59-65 pubmed
    ..The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed. ..
  40. Thomer M, May N, Aggarwal B, Kwok G, Calvi B. Drosophila double-parked is sufficient to induce re-replication during development and is regulated by cyclin E/CDK2. Development. 2004;131:4807-18 pubmed
    ..In the context of findings from human and other cells, our results indicate that stringent regulation of Dup protein is critical to protect genome integrity. ..
  41. de la Motte S, Gianella Borradori A. Pharmacokinetic model of R-roscovitine and its metabolite in healthy male subjects. Int J Clin Pharmacol Ther. 2004;42:232-9 pubmed
    ..The compartmental analysis clarified important pharmacokinetic aspects relevant for the clinical development of the compound. ..
  42. Gil Gomez G. Measurement of changes in apoptosis and cell cycle regulatory kinase Cdk2. Methods Mol Biol. 2004;282:131-44 pubmed
    ..Methods for measuring Cdk2 changes in activity in quiescent cells undergoing apoptosis are detailed in this chapter. ..
  43. Oshiro C, Bradley E, Eksterowicz J, Evensen E, Lamb M, Lanctot J, et al. Performance of 3D-database molecular docking studies into homology models. J Med Chem. 2004;47:764-7 pubmed
    ..This performance is comparable to docking to crystal structures. ..
  44. Sachs N, Vaillancourt R. Cyclin-dependent kinase 11p110 and casein kinase 2 (CK2) inhibit the interaction between tyrosine hydroxylase and 14-3-3. J Neurochem. 2004;88:51-62 pubmed
  45. Deng X, Gao F, May W. Bcl2 retards G1/S cell cycle transition by regulating intracellular ROS. Blood. 2003;102:3179-85 pubmed
    ..Furthermore, phosphorylation of Bcl2 may functionally link its antiapoptotic, cell cycle retardation, and antioxidant properties. ..
  46. Ohlson L, Koroxenidou L, Porsch Hällström I. Mitoinhibitory effects of the tumor promoter 2-acetylaminofluorene in rat liver: loss of E2F-1 and E2F-3 expression and cdk 2 kinase activity in late G1. J Hepatol. 2004;40:957-62 pubmed
    ..Examine the mitoinhibitory effect of the liver tumor promoter 2-acetylaminofluorene (2-AAF) in vivo, with focus on the proteins regulating G1- and S progression...
  47. Park H, Yeom M, Lee S. Loop flexibility and solvent dynamics as determinants for the selective inhibition of cyclin-dependent kinase 4: comparative molecular dynamics simulation studies of CDK2 and CDK4. Chembiochem. 2004;5:1662-72 pubmed
  48. Lee S, McCormick F. Downregulation of Skp2 and p27/Kip1 synergistically induces apoptosis in T98G glioblastoma cells. J Mol Med (Berl). 2005;83:296-307 pubmed
    ..We suggest that Skp2 in tumor cells suppresses apoptosis through Bcl-2 expression, potentially through regulation of cyclin E-CDK2 activity. ..
  49. Tomita N, Kim J, Gibbons G, Zhang L, Kaneda Y, Stahl R, et al. Gene therapy with an E2F transcription factor decoy inhibits cell cycle progression in rat anti-Thy 1 glomerulonephritis. Int J Mol Med. 2004;13:629-36 pubmed
    ..These data also demonstrate the feasibility and the potential benefit of in vivo gene therapy as a novel strategy in the treatment of glomerular diseases. ..
  50. Ham Y, Choi K, Song S, Jin Y, Chun M, Lee S. Xylocydine, a novel inhibitor of cyclin-dependent kinases, prevents the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptotic cell death of SK-HEP-1 cells. J Pharmacol Exp Ther. 2004;308:814-9 pubmed
    ..Xylocydine is thus a novel and potent CDK inhibitor that could be used to interfere with cell cycle- and apoptosis-related CDK activity in various diseases. ..
  51. Umeyama T, Kaneko A, Niimi M, Uehara Y. Repression of CDC28 reduces the expression of the morphology-related transcription factors, Efg1p, Nrg1p, Rbf1p, Rim101p, Fkh2p and Tec1p and induces cell elongation in Candida albicans. Yeast. 2006;23:537-52 pubmed
    ..Taken together, these data indicate that repression of CDC28 affected the protein levels of the morphology-related transcription factors, the regulation of hyphae-specific genes and cell shape in C. albicans. ..
  52. Jiang W, Zhu Z, Thompson H. Effect of energy restriction on cell cycle machinery in 1-methyl-1-nitrosourea-induced mammary carcinomas in rats. Cancer Res. 2003;63:1228-34 pubmed
  53. Margolis S, Kornbluth S. When the checkpoints have gone: insights into Cdc25 functional activation. Cell Cycle. 2004;3:425-8 pubmed
    ..Here we integrate our findings and those of others to propose a model for Cdc25 activation in an effort to provide insight into novel loci of DNA-responsive checkpoint control of mitotic entry. ..