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Gene Review

CDK1  -  cyclin-dependent kinase 1

Homo sapiens

Synonyms: CDC2, CDC28A, CDKN1, Cell division control protein 2 homolog, Cell division protein kinase 1, ...
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Disease relevance of CDC2


Psychiatry related information on CDC2


High impact information on CDC2

  • The mitotic regulators Wee1 and Cdk1 can inactivate each other through inhibitory phosphorylations [8].
  • Here, we show that CDK phosphorylation of the essential licensing factor Cdc6 stabilizes it by preventing its association with the anaphase promoting complex/cyclosome (APC/C) [9].
  • The surprising redundancy amongst the classical cyclins (A, B, and E) and cyclin-dependent kinases (Cdk1 and Cdk2) show that the important differences between these proteins are when and where they are expressed rather than the proteins they phosphorylate [10].
  • We found that initial activation of Aurora-A in late G2 phase of the cell cycle is essential for recruitment of the cyclin B1-Cdk1 complex to centrosomes, where it becomes activated and commits cells to mitosis [11].
  • Our results indicate that Cdk1-dependent spindle asymmetry ensures proper alignment of the mitotic spindle with the cell division axis [12].

Chemical compound and disease context of CDC2


Biological context of CDC2


Anatomical context of CDC2


Associations of CDC2 with chemical compounds


Physical interactions of CDC2


Enzymatic interactions of CDC2

  • CDC25B phosphatase plays a key role in controlling G2-M progression by dephosphorylating two inhibitory residues of CDC2 and also has been suggested to have an oncogenic property [24].
  • In addition, GA-treated cells were shown to have a low level of CDK7 kinase-phosphorylated-Thr(161) CDC2/p34 (active) [34].
  • We identified that Thr85 immediately prior to the NLS of PTHrP was phosphorylated by CDC2-CDK2 and phosphorylation was cell cycle-dependent [35].
  • These findings reveal that Dab2 is differentially phosphorylated during the cell cycle by cdc2 and provide a potential feedback mechanism by which Dab2 inhibition of cell growth and proliferation may be regulated [36].
  • In contrast with ATR-Seckel syndrome cells, MCPH1-mutant cells have low levels of Tyr 15-phosphorylated Cdk1 (pY15-Cdk1) in S and G2 phases, which correlates with an elevated frequency of G2-like cells displaying premature chromosome condensation (PCC) [37].

Regulatory relationships of CDC2

  • The STAT signaling pathway appears to negatively regulate the cell cycle by inducing CDK inhibitors in response to cytokines [38].
  • Thus, hyperphosphorylated p21 activates the Cdc2 kinase in the G2/M transition [31].
  • These results indicate that the T-loop not only plays a key role in keeping a free CDK in its inactive state but also in facilitating CDK activation by promoting cyclin binding [2].
  • Such high levels of p16INK4a/p18INK4c should normally inhibit cyclin-dependent kinase (CDK) 4 and 6 activities in cells containing functional pRb, delaying cell cycle progression and growth [39].
  • Intriguingly, the subclass exemplified by the melanoma-derived N50S mutant may promote tumorigenesis, by both attenuating CDK-inhibitory function and concomitantly activating the proto-oncogenic cyclin D-dependent kinases [40].

Other interactions of CDC2


Analytical, diagnostic and therapeutic context of CDC2


  1. CDP/cut is the DNA-binding subunit of histone gene transcription factor HiNF-D: a mechanism for gene regulation at the G1/S phase cell cycle transition point independent of transcription factor E2F. van Wijnen, A.J., van Gurp, M.F., de Ridder, M.C., Tufarelli, C., Last, T.J., Birnbaum, M., Vaughan, P.S., Giordano, A., Krek, W., Neufeld, E.J., Stein, J.L., Stein, G.S. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  2. T-loop deletion of CDC2 from breast cancer tissues eliminates binding to cyclin B1 and cyclin-dependent kinase inhibitor p21. Ohta, T., Okamoto, K., Isohashi, F., Shibata, K., Fukuda, M., Yamaguchi, S., Xiong, Y. Cancer Res. (1998) [Pubmed]
  3. Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma. Guo, J., Kleeff, J., Li, J., Ding, J., Hammer, J., Zhao, Y., Giese, T., Korc, M., Büchler, M.W., Friess, H. Oncogene (2004) [Pubmed]
  4. Dissecting the Roles of Checkpoint Kinase 1/CDC2 and Mitogen-Activated Protein Kinase Kinase 1/2/Extracellular Signal-Regulated Kinase 1/2 in Relation to 7-Hydroxystaurosporine-Induced Apoptosis in Human Multiple Myeloma Cells. Pei, X.Y., Li, W., Dai, Y., Dent, P., Grant, S. Mol. Pharmacol. (2006) [Pubmed]
  5. Inhibition of X-ray and doxorubicin-induced apoptosis by butyrolactone I, a CDK-specific inhibitor, in human tumor cells. Lu, Y., Takebe, H., Yagi, T. J. Radiat. Res. (2000) [Pubmed]
  6. Cyclin-dependent kinase inhibitors: cancer killers to neuronal guardians. Monaco, E.A., Vallano, M.L. Current medicinal chemistry. (2003) [Pubmed]
  7. Cell cycle regulation of central spindle assembly. Mishima, M., Pavicic, V., Grüneberg, U., Nigg, E.A., Glotzer, M. Nature (2004) [Pubmed]
  8. Substrate competition as a source of ultrasensitivity in the inactivation of wee1. Kim, S.Y., Ferrell, J.E. Cell (2007) [Pubmed]
  9. CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Mailand, N., Diffley, J.F. Cell (2005) [Pubmed]
  10. Recycling the cell cycle: cyclins revisited. Murray, A.W. Cell (2004) [Pubmed]
  11. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Hirota, T., Kunitoku, N., Sasayama, T., Marumoto, T., Zhang, D., Nitta, M., Hatakeyama, K., Saya, H. Cell (2003) [Pubmed]
  12. Asymmetric loading of Kar9 onto spindle poles and microtubules ensures proper spindle alignment. Liakopoulos, D., Kusch, J., Grava, S., Vogel, J., Barral, Y. Cell (2003) [Pubmed]
  13. Perifosine, a novel alkylphospholipid, induces p21(WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest. Patel, V., Lahusen, T., Sy, T., Sausville, E.A., Gutkind, J.S., Senderowicz, A.M. Cancer Res. (2002) [Pubmed]
  14. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. Prall, O.W., Sarcevic, B., Musgrove, E.A., Watts, C.K., Sutherland, R.L. J. Biol. Chem. (1997) [Pubmed]
  15. Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Watts, C.K., Brady, A., Sarcevic, B., deFazio, A., Musgrove, E.A., Sutherland, R.L. Mol. Endocrinol. (1995) [Pubmed]
  16. Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Kim, E.H., Kim, H.S., Kim, S.U., Noh, E.J., Lee, J.S., Choi, K.S. Oncogene (2005) [Pubmed]
  17. Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Ahmad, N., Adhami, V.M., Afaq, F., Feyes, D.K., Mukhtar, H. Clin. Cancer Res. (2001) [Pubmed]
  18. Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. Gu, Y., Rosenblatt, J., Morgan, D.O. EMBO J. (1992) [Pubmed]
  19. Cdc25M2 activation of cyclin-dependent kinases by dephosphorylation of threonine-14 and tyrosine-15. Sebastian, B., Kakizuka, A., Hunter, T. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  20. A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. Ye, X., Zhu, C., Harper, J.W. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  21. Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage. Kandel, E.S., Skeen, J., Majewski, N., Di Cristofano, A., Pandolfi, P.P., Feliciano, C.S., Gartel, A., Hay, N. Mol. Cell. Biol. (2002) [Pubmed]
  22. Cell cycle regulation of human WEE1. McGowan, C.H., Russell, P. EMBO J. (1995) [Pubmed]
  23. Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Rosenblatt, J., Gu, Y., Morgan, D.O. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  24. Overexpression of CDC25B overrides radiation-induced G2-M arrest and results in increased apoptosis in esophageal cancer cells. Miyata, H., Doki, Y., Yamamoto, H., Kishi, K., Takemoto, H., Fujiwara, Y., Yasuda, T., Yano, M., Inoue, M., Shiozaki, H., Weinstein, I.B., Monden, M. Cancer Res. (2001) [Pubmed]
  25. G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with exponentially decreasing low-dose-rate gamma radiation. Ning, S., Knox, S.J. Radiat. Res. (1999) [Pubmed]
  26. Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Levkau, B., Koyama, H., Raines, E.W., Clurman, B.E., Herren, B., Orth, K., Roberts, J.M., Ross, R. Mol. Cell (1998) [Pubmed]
  27. Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2. Desai, D., Wessling, H.C., Fisher, R.P., Morgan, D.O. Mol. Cell. Biol. (1995) [Pubmed]
  28. Differential contribution of inhibitory phosphorylation of CDC2 and CDK2 for unperturbed cell cycle control and DNA integrity checkpoints. Chow, J.P., Siu, W.Y., Ho, H.T., Ma, K.H., Ho, C.C., Poon, R.Y. J. Biol. Chem. (2003) [Pubmed]
  29. Modulation of Sp1 activity by a cyclin A/CDK complex. Haidweger, E., Novy, M., Rotheneder, H. J. Mol. Biol. (2001) [Pubmed]
  30. Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1. Moore, J.D., Yang, J., Truant, R., Kornbluth, S. J. Cell Biol. (1999) [Pubmed]
  31. Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Dash, B.C., El-Deiry, W.S. Mol. Cell. Biol. (2005) [Pubmed]
  32. Analysis of wild-type and mutant p21WAF-1 gene activities. Lin, J., Reichner, C., Wu, X., Levine, A.J. Mol. Cell. Biol. (1996) [Pubmed]
  33. c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mateyak, M.K., Obaya, A.J., Sedivy, J.M. Mol. Cell. Biol. (1999) [Pubmed]
  34. Gambogic acid-induced G2/M phase cell-cycle arrest via disturbing CDK7-mediated phosphorylation of CDC2/p34 in human gastric carcinoma BGC-823 cells. Yu, J., Guo, Q.L., You, Q.D., Zhao, L., Gu, H.Y., Yang, Y., Zhang, H.W., Tan, Z., Wang, X. Carcinogenesis (2007) [Pubmed]
  35. Phosphorylation at the cyclin-dependent kinases site (Thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization. Lam, M.H., House, C.M., Tiganis, T., Mitchelhill, K.I., Sarcevic, B., Cures, A., Ramsay, R., Kemp, B.E., Martin, T.J., Gillespie, M.T. J. Biol. Chem. (1999) [Pubmed]
  36. Cell cycle-dependent phosphorylation of Disabled-2 by cdc2. He, J., Xu, J., Xu, X.X., Hall, R.A. Oncogene (2003) [Pubmed]
  37. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Alderton, G.K., Galbiati, L., Griffith, E., Surinya, K.H., Neitzel, H., Jackson, A.P., Jeggo, P.A., O'Driscoll, M. Nat. Cell Biol. (2006) [Pubmed]
  38. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Chin, Y.E., Kitagawa, M., Su, W.C., You, Z.H., Iwamoto, Y., Fu, X.Y. Science (1996) [Pubmed]
  39. Disruption of the cyclin D/cyclin-dependent kinase/INK4/retinoblastoma protein regulatory pathway in human neuroblastoma. Easton, J., Wei, T., Lahti, J.M., Kidd, V.J. Cancer Res. (1998) [Pubmed]
  40. p21WAF1/CIP1 mutants deficient in inhibiting cyclin-dependent kinases (CDKs) can promote assembly of active cyclin D/CDK4(6) complexes in human tumor cells. Welcker, M., Lukas, J., Strauss, M., Bartek, J. Cancer Res. (1998) [Pubmed]
  41. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Dulić, V., Kaufmann, W.K., Wilson, S.J., Tlsty, T.D., Lees, E., Harper, J.W., Elledge, S.J., Reed, S.I. Cell (1994) [Pubmed]
  42. Cdk-activating kinase complex is a component of human transcription factor TFIIH. Shiekhattar, R., Mermelstein, F., Fisher, R.P., Drapkin, R., Dynlacht, B., Wessling, H.C., Morgan, D.O., Reinberg, D. Nature (1995) [Pubmed]
  43. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Russo, A.A., Tong, L., Lee, J.O., Jeffrey, P.D., Pavletich, N.P. Nature (1998) [Pubmed]
  44. Association of human cyclin E with a periodic G1-S phase protein kinase. Dulić, V., Lees, E., Reed, S.I. Science (1992) [Pubmed]
  45. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Montagnoli, A., Fiore, F., Eytan, E., Carrano, A.C., Draetta, G.F., Hershko, A., Pagano, M. Genes Dev. (1999) [Pubmed]
  46. Regulation of cyclin-dependent kinase 2 activity by ceramide. Lee, J.Y., Bielawska, A.E., Obeid, L.M. Exp. Cell Res. (2000) [Pubmed]
  47. Regional assignment of the human cell cycle control gene CDC2 to chromosome 10q21 by in situ hybridization. Nazarenko, S.A., Ostroverhova, N.V., Spurr, N.K. Hum. Genet. (1991) [Pubmed]
  48. A cyclin-dependent kinase inhibitor inducing cancer cell differentiation: biochemical identification using Xenopus egg extracts. Rosania, G.R., Merlie, J., Gray, N., Chang, Y.T., Schultz, P.G., Heald, R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  49. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Kriwacki, R.W., Hengst, L., Tennant, L., Reed, S.I., Wright, P.E. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  50. UCN-01-induced cell cycle arrest requires the transcriptional induction of p21(waf1/cip1) by activation of mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. Facchinetti, M.M., De Siervi, A., Toskos, D., Senderowicz, A.M. Cancer Res. (2004) [Pubmed]
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