cyclin dependent kinase 2

Summary

Summary: A key regulator of CELL CYCLE progression. It partners with CYCLIN E to regulate entry into S PHASE and also interacts with CYCLIN A to phosphorylate RETINOBLASTOMA PROTEIN. Its activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P27 and CYCLIN-DEPENDENT KINASE INHIBITOR P21.

Top Publications

  1. Machida Y, Teer J, Dutta A. Acute reduction of an origin recognition complex (ORC) subunit in human cells reveals a requirement of ORC for Cdk2 activation. J Biol Chem. 2005;280:27624-30 pubmed
    ..These results demonstrate an unexpected role of ORC2 in CDK2 activation, a linkage that could be important for maintaining genomic stability. ..
  2. Myers J, Zhao R, Xu X, Ham A, Cortez D. Cyclin-dependent kinase 2 dependent phosphorylation of ATRIP regulates the G2-M checkpoint response to DNA damage. Cancer Res. 2007;67:6685-90 pubmed
    ..Thus, ATRIP is a CDK2 substrate, and CDK2-dependent phosphorylation of S224 regulates the ability of ATR-ATRIP to promote cell cycle arrest in response to DNA damage. ..
  3. Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge S, et al. SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev. 2003;17:3062-74 pubmed
    ..These data indicate that Cdc25A turnover is more complex than previously appreciated and suggest roles for an additional kinase(s) in Chk1-dependent Cdc25A turnover. ..
  4. Nevis K, Cordeiro Stone M, Cook J. Origin licensing and p53 status regulate Cdk2 activity during G(1). Cell Cycle. 2009;8:1952-63 pubmed
    ..These results demonstrate dependence on origin licensing for multiple events required for G(1) progression, and suggest a mechanism to prevent premature S phase entry that functions in normal cells but not in p53-deficient cells. ..
  5. Hydbring P, Bahram F, Su Y, Tronnersjö S, Högstrand K, von der Lehr N, et al. Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. Proc Natl Acad Sci U S A. 2010;107:58-63 pubmed publisher
    ..Finally, our findings highlight that pharmacological inhibition of Cdk2 activity is a potential therapeutical principle for cancer therapy, in particular for tumors with activated Myc or Ras. ..
  6. Mateo F, Vidal Laliena M, Canela N, Busino L, Martinez Balbas M, Pagano M, et al. Degradation of cyclin A is regulated by acetylation. Oncogene. 2009;28:2654-66 pubmed publisher
    ..All these results indicate that cyclin A acetylation at specific lysines is crucial for cyclin A stability and also has a function in the regulation of cycA-cdk activity. ..
  7. Campaner S, Doni M, Hydbring P, Verrecchia A, Bianchi L, Sardella D, et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol. 2010;12:54-9; sup pp 1-14 pubmed publisher
    ..Pharmacological inhibition of Cdk2 induced Myc-dependent senescence in various cell types, including a p53-null human cancer cell line. Our data warrant re-assessment of Cdk2 as a therapeutic target in Myc- or Wnt-driven tumours. ..
  8. Paolinelli R, Mendoza Maldonado R, Cereseto A, Giacca M. Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Nat Struct Mol Biol. 2009;16:412-20 pubmed publisher
    ..This two-step, intramolecular regulatory program by sequential modification of CDC6 seems to be essential for proper S-phase progression. ..
  9. Helal C, Kang Z, Lucas J, Gant T, Ahlijanian M, Schachter J, et al. Potent and cellularly active 4-aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer's disease. Bioorg Med Chem Lett. 2009;19:5703-7 pubmed publisher
    ..SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E. ..

More Information

Publications62

  1. Cho S, Lee S, Kim Y, Park B, Choi J, Liu L, et al. Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. Cancer Lett. 2010;287:196-206 pubmed publisher
    ..Taken together, these data suggest that the novel Cdk inhibitor xylocydine is a good candidate for an anti-cancer drug for HCC therapy. ..
  2. Hu J, Cai X, Yan G. Alphavirus M1 induces apoptosis of malignant glioma cells via downregulation and nucleolar translocation of p21WAF1/CIP1 protein. Cell Cycle. 2009;8:3328-39 pubmed
    ..Altogether, downregulation and nucleolar translocation of the p21(WAF1/CIP1) protein played an active role in M1-induced C6 apoptosis. ..
  3. Adon A, Zeng X, Harrison M, Sannem S, Kiyokawa H, Kaldis P, et al. Cdk2 and Cdk4 regulate the centrosome cycle and are critical mediators of centrosome amplification in p53-null cells. Mol Cell Biol. 2010;30:694-710 pubmed publisher
  4. Wingate H, Puskas A, Duong M, Bui T, Richardson D, Liu Y, et al. Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression. Cell Cycle. 2009;8:1062-8 pubmed
    ..The LMW isoforms of cyclin E are tumor specific, and are biochemically and biologically distinct from the full-length cyclin E which could provide a novel role in breast cancer progression. ..
  5. Win H, Acevedo Duncan M. Role of protein kinase C-iota in transformed non-malignant RWPE-1 cells and androgen-independent prostate carcinoma DU-145 cells. Cell Prolif. 2009;42:182-94 pubmed publisher
  6. Lee W, Choi J, Byun M, Koo K, Shin S, Lee S, et al. Functional inactivation of triosephosphate isomerase through phosphorylation during etoposide-induced apoptosis in HeLa cells: potential role of Cdk2. Toxicology. 2010;278:224-8 pubmed publisher
    ..Loss of catalytic activity of TPI as a consequence of phosphorylation of this glycolytic enzyme may disrupt energy production in etoposide-treated HeLa cells, rendering these cells prone to undergo apoptosis. ..
  7. Estrela P, Paul D, Song Q, Stadler L, Wang L, Huq E, et al. Label-free sub-picomolar protein detection with field-effect transistors. Anal Chem. 2010;82:3531-6 pubmed publisher
    ..The target specificity, ease of fabrication, and scalability of these FET arrays further demonstrate the potential application of the multiplexable field effect format to protein sensing. ..
  8. Chen S, Law C, Gardner D. Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity. J Steroid Biochem Mol Biol. 2010;118:135-41 pubmed publisher
  9. Ibrahim D, El Metwally A. Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors. Eur J Med Chem. 2010;45:1158-66 pubmed publisher
    ..The design, synthesis and biological evaluation of these 2,4,5,6-tetrasubstituted pyrimidine derivatives are reported. ..
  10. Perrard M, Chassaing E, Montillet G, Sabido O, Durand P. Cytostatic factor proteins are present in male meiotic cells and beta-nerve growth factor increases mos levels in rat late spermatocytes. PLoS ONE. 2009;4:e7237 pubmed publisher
    ..In addition, they reinforce the view that NGF, by enhancing Mos in late spermatocytes, is one of the intra-testicular factors which adjusts the number of round spermatids that can be supported by Sertoli cells. ..
  11. Penela P, Rivas V, Salcedo A, Mayor F. G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proc Natl Acad Sci U S A. 2010;107:1118-23 pubmed publisher
  12. Kumar S, Biancotti J, Matalon R, de Vellis J. Lack of aspartoacylase activity disrupts survival and differentiation of neural progenitors and oligodendrocytes in a mouse model of Canavan disease. J Neurosci Res. 2009;87:3415-27 pubmed publisher
    ..We also report an early expression of full-length ASPA mRNA in normal mouse brain at embryonic day 12.5, when OL progenitors first appear during development. These findings support involvement of ASPA in CNS development and function. ..
  13. Wesierska Gadek J, Krystof V. Selective cyclin-dependent kinase inhibitors discriminating between cell cycle and transcriptional kinases: future reality or utopia?. Ann N Y Acad Sci. 2009;1171:228-41 pubmed publisher
    ..In this article the action and specificity of CDK inhibitor roscovitine, belonging to the group of purine analogues, is reviewed and the rationale for dissecting the inhibitory action on cell cycle and transcriptional CDKs is discussed. ..
  14. Huang D, Caflisch A. Library screening by fragment-based docking. J Mol Recognit. 2010;23:183-93 pubmed publisher
  15. Beamish H, de Boer L, Giles N, Stevens F, Oakes V, Gabrielli B. Cyclin A/cdk2 regulates adenomatous polyposis coli-dependent mitotic spindle anchoring. J Biol Chem. 2009;284:29015-23 pubmed publisher
    ..Mutation of APC Ser-1360 to Ala results in identical off-centered mitotic spindles. Thus, this cyclin A/cdk2-dependent phosphorylation of APC affects astral microtubule attachment to the cortical surface in mitosis. ..
  16. Nair B, Nair S, Chakravarty D, Challa R, Manavathi B, Yew P, et al. Cyclin-dependent kinase-mediated phosphorylation plays a critical role in the oncogenic functions of PELP1. Cancer Res. 2010;70:7166-75 pubmed publisher
    ..Because the expression of both PELP1 and CDKs is deregulated in breast tumors, CDK-PELP1 interactions will have implications in breast cancer progression. ..
  17. Byth K, Thomas A, Hughes G, Forder C, McGregor A, Geh C, et al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol Cancer Ther. 2009;8:1856-66 pubmed publisher
    ..These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise. ..
  18. Aubry C, Wilson A, Emmerson D, Murphy E, Chan Y, Dickens M, et al. Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1. Bioorg Med Chem. 2009;17:6073-84 pubmed publisher
    ..We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC(50) for the best compounds 10m and 13a being 39 and 37microm, respectively. ..
  19. Casado Vela J, Martínez Torrecuadrada J, Casal J. Differential phosphorylation patterns between the Cyclin-A2/CDK2 complex and their monomers. Protein Expr Purif. 2009;66:15-21 pubmed publisher
  20. Kazi A, Carie A, Blaskovich M, Bucher C, Thai V, Moulder S, et al. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol. 2009;29:2254-63 pubmed publisher
    ..Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27(Kip1) levels. ..
  21. Buttitta L, Katzaroff A, Edgar B. A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo. J Cell Biol. 2010;189:981-96 pubmed publisher
    ..These mechanisms are essential for proper development, as evading them leads to tissue outgrowths composed of dividing but terminally differentiated cells. ..
  22. Anderson D, Meyers M, Kurumbail R, Caspers N, Poda G, Long S, et al. Benzothiophene inhibitors of MK2. Part 1: structure-activity relationships, assessments of selectivity and cellular potency. Bioorg Med Chem Lett. 2009;19:4878-81 pubmed publisher
    ..Crystallographic data provide a rationale for the observed MK2 potency as well as selectivity over CDK2 for this class of inhibitors. ..
  23. Caldon C, Sergio C, Schütte J, Boersma M, Sutherland R, Carroll J, et al. Estrogen regulation of cyclin E2 requires cyclin D1 but not c-Myc. Mol Cell Biol. 2009;29:4623-39 pubmed publisher
    ..This contrasts with the predominant regulation of cyclin E1-Cdk2 activity via CDK inhibitor association downstream of both c-Myc and cyclin D1 and indicates that cyclins E1 and E2 are not always coordinately regulated. ..
  24. Goode E, Fridley B, Vierkant R, Cunningham J, Phelan C, Anderson S, et al. Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk. Cancer Epidemiol Biomarkers Prev. 2009;18:935-44 pubmed publisher
    ..These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls. ..
  25. Bento C, Andersson M, Aman P. DDIT3/CHOP and the sarcoma fusion oncoprotein FUS-DDIT3/TLS-CHOP bind cyclin-dependent kinase 2. BMC Cell Biol. 2009;10:89 pubmed publisher
    ..We conclude that DDIT3 binds CDK2 and that many of the observed biological effects of DDIT3 may involve interaction with CDK2. ..
  26. Pearce B, Langley D, Kang J, Huang H, Kulkarni A. E-novo: an automated workflow for efficient structure-based lead optimization. J Chem Inf Model. 2009;49:1797-809 pubmed publisher
    ..The E-Novo protocol provides a convenient all-in-one structure-based design process for rapid assessment and scoring of lead optimization libraries. ..
  27. Johnson K, Tan M, Sutterlin C. Centrosome abnormalities during a Chlamydia trachomatis infection are caused by dysregulation of the normal duplication pathway. Cell Microbiol. 2009;11:1064-73 pubmed publisher
    ..However, C. trachomatis induces a loss of numerical control so that multiple procentrioles are formed per template. ..
  28. Moody C, Laimins L. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10:550-60 pubmed publisher
    ..Understanding how HPV oncoproteins modify these activities provides novel insights into the basic mechanisms of oncogenesis. ..
  29. Llado V, Gutierrez A, Martínez J, CASAS J, Terés S, Higuera M, et al. Minerval induces apoptosis in Jurkat and other cancer cells. J Cell Mol Med. 2010;14:659-70 pubmed publisher
    ..This is the first report on the pro-apoptotic activity of Minerval, and in part explains the effectiveness of this non-toxic anticancer drug and its wide spectrum against different types of cancer. ..
  30. Singh P, Kumar R, Sharma A, Arora R, Chawla R, Jain S, et al. Podophyllum hexandrum fraction (REC-2006) shows higher radioprotective efficacy in the p53-carrying hepatoma cell line: a role of cell cycle regulatory proteins. Integr Cancer Ther. 2009;8:261-72 pubmed publisher
  31. Shalaby T, Von Bueren A, Hürlimann M, Fiaschetti G, Castelletti D, Masayuki T, et al. Disabling c-Myc in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadruplex interactive agent S2T1-6OTD. Mol Cancer Ther. 2010;9:167-79 pubmed publisher
    ..On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors...
  32. Jiang W, Zhong Z, Nguyen A, Henson J, Toouli C, Braithwaite A, et al. Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins. J Cell Biol. 2009;185:797-810 pubmed publisher
  33. Mitchell K, Wilson S, Elferink C. The activated aryl hydrocarbon receptor synergizes mitogen-induced murine liver hyperplasia. Toxicology. 2010;276:103-9 pubmed publisher
    ..These findings are in stark contrast to previous observations that the activated AhR can suppress hepatocyte proliferation in vivo and reveal a new complexity to AhR-mediated cell cycle control. ..
  34. Wang S, Li Y. Expression of constitutively active cGMP-dependent protein kinase inhibits glucose-induced vascular smooth muscle cell proliferation. Am J Physiol Heart Circ Physiol. 2009;297:H2075-83 pubmed publisher
  35. Kisielewska J, Philipova R, Huang J, Whitaker M. MAP kinase dependent cyclinE/cdk2 activity promotes DNA replication in early sea urchin embryos. Dev Biol. 2009;334:383-94 pubmed publisher
    ..This pattern of regulation of DNA synthesis conforms to the pattern observed in mammalian somatic cells. ..
  36. Hseu Y, Lin E, Chen J, Liua Y, Huang C, Lu F, et al. Humic acid induces G1 phase arrest and apoptosis in cultured vascular smooth muscle cells. Environ Toxicol. 2009;24:243-58 pubmed publisher
    ..Our findings suggest that HA-induced DNA damage, cell cycle arrest, and apoptosis in SMCs may be an underlying mechanisms for the atherosclerosis and thrombosis observed in the BFD endemic region. ..
  37. Tane S, Chibazakura T. Cyclin A overexpression induces chromosomal double-strand breaks in mammalian cells. Cell Cycle. 2009;8:3900-3 pubmed
    ..Moreover, the gamma-H2AX focus formation was suppressed by co-expressing p21(Cip1/Waf1) or dominant-negative Cdk2 mutant, suggesting that aberrant cyclin A-Cdk2 activation induces the chromosomal double-strand breaks. ..
  38. DELK N, Hunt K, Keyomarsi K. Altered subcellular localization of tumor-specific cyclin E isoforms affects cyclin-dependent kinase 2 complex formation and proteasomal regulation. Cancer Res. 2009;69:2817-25 pubmed publisher
    ..One implication of our findings is that altered LMW-E and LMW-E/Cdk2 subcellular localization may lead to aberrant LMW-E protein interactions, regulation, and activity, ultimately contributing to LMW-E tumorigenicity. ..
  39. Chen Y, Zheng J, Zhang Y, Wang J, Liu Q, Huang Z, et al. N-4-tert-butyl benzyl haloperidol chloride suppresses Ca2+-dependent Egr-1 expression and subsequently inhibits vascular smooth muscle cell proliferation induced by angiotensin II. Cell Physiol Biochem. 2009;23:295-304 pubmed publisher
    ..Egr-1 may play a key role in Ang II-induced proliferation of VSMCs. C(3) inhibits vascular smooth muscle cell proliferation and the mechanism is involved with the inhibition of over-expression of Egr-1. ..
  40. Hydbring P, Larsson L. Tipping the balance: Cdk2 enables Myc to suppress senescence. Cancer Res. 2010;70:6687-91 pubmed publisher
  41. Kamal A, Dastagiri D, Ramaiah M, Bharathi E, Reddy J, Balakishan G, et al. Synthesis, anticancer activity and mitochondrial mediated apoptosis inducing ability of 2,5-diaryloxadiazole-pyrrolobenzodiazepine conjugates. Bioorg Med Chem. 2010;18:6666-77 pubmed publisher
    ..Some detailed biological assays relating to the cell cycle aspects associated to Bax and caspases have been examined with a view to understand the mechanism of action of these conjugates. ..
  42. Tang H, Tan G, Guo Q, Pang R, Zeng F. Abnormal activation of the Akt-GSK3beta signaling pathway in peripheral blood T cells from patients with systemic lupus erythematosus. Cell Cycle. 2009;8:2789-93 pubmed
    ..Abnormal activation of the Akt-GSK3beta signaling pathway increased the proliferation of lupus lymphocytes. ..
  43. Saxena U, Powell C, Fecko J, Cacioppo R, Chou H, Cooper G, et al. Phosphorylation by cyclin C/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of LSF during G1 progression. Mol Cell Biol. 2009;29:2335-45 pubmed publisher
    ..Unexpectedly, this phosphorylation prevents induction of LSF target genes until late G(1). ..
  44. Schuliga M, See I, Ong S, Soon L, Camoretti Mercado B, Harris T, et al. Fibrillar collagen clamps lung mesenchymal cells in a nonproliferative and noncontractile phenotype. Am J Respir Cell Mol Biol. 2009;41:731-41 pubmed publisher
    ..fCollagen appears to apply a phenotypic clamp on lung fibroblasts that may be partially released by autocrine MMP activity. ..
  45. Cobianchi S, Marinelli S, Florenzano F, Pavone F, Luvisetto S. Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury. Neuroscience. 2010;168:273-87 pubmed publisher
  46. Flores O, Wang Z, Knudsen K, Burnstein K. Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition. Endocrinology. 2010;151:896-908 pubmed publisher
    ..These data establish central roles for CDK2 nuclear-cytoplasmic trafficking and cyclin E in the mechanism of 1,25-(OH)(2)D(3)-mediated growth inhibition in prostate cancer cells. ..
  47. Mateo F, Vidal Laliena M, Pujol M, Bachs O. Acetylation of cyclin A: a new cell cycle regulatory mechanism. Biochem Soc Trans. 2010;38:83-6 pubmed publisher
    ..Interestingly, these four lysine residues in cyclin A also participate in the regulation of cyclin A-Cdk (cyclin-dependent kinase) activity by modulating its interaction with Cdks. ..
  48. Quesenberry P, Dooner G, Tatto M, Colvin G, Johnson K, Dooner M. Expression of cell cycle-related genes with cytokine-induced cell cycle progression of primitive hematopoietic stem cells. Stem Cells Dev. 2010;19:453-60 pubmed publisher
    ..The alterations in multiple other cell cycle regulators were consistent with previous information obtained in other cell systems. The cycle regulatory mechanics appears to be preserved across broad ranges of cell types. ..
  49. Van Hoof D, Munoz J, Braam S, Pinkse M, Linding R, Heck A, et al. Phosphorylation dynamics during early differentiation of human embryonic stem cells. Cell Stem Cell. 2009;5:214-26 pubmed publisher
    ..The findings provide new insights into how hESCs exit the pluripotent state and present the hESC (phospho)proteome resource as a complement to existing pluripotency network databases. ..
  50. Zaveri N, Sato B, Jiang F, Calaoagan J, Laderoute K, Murphy B. A novel peroxisome proliferator-activated receptor delta antagonist, SR13904, has anti-proliferative activity in human cancer cells. Cancer Biol Ther. 2009;8:1252-61 pubmed
  51. Kumar S, Barthwal M, Dikshit M. Cdk2 nitrosylation and loss of mitochondrial potential mediate NO-dependent biphasic effect on HL-60 cell cycle. Free Radic Biol Med. 2010;48:851-61 pubmed publisher
    ..This study demonstrates that the DETA-NO-mediated biphasic effect was dependent on Cdk2 nitrosylation/activation and the loss of mitochondrial potential at low and high concentrations, respectively. ..
  52. Paulitschke V, Schicher N, Szekeres T, Jäger W, Elbling L, Riemer A, et al. 3,3',4,4',5,5'-hexahydroxystilbene impairs melanoma progression in a metastatic mouse model. J Invest Dermatol. 2010;130:1668-79 pubmed publisher
    ..In summary, M8 exerts strong antitumor effects with the potential to become a new drug for the treatment of metastatic melanoma. ..
  53. Mull B, Cox J, Bui T, Keyomarsi K. Post-translational modification and stability of low molecular weight cyclin E. Oncogene. 2009;28:3167-76 pubmed publisher
    ..The stability of low molecular weight cyclin E may have implications for both tumorigenesis and treatment of tumors expressing them. ..