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Cdk2  -  cyclin dependent kinase 2

Rattus norvegicus

Synonyms: Cdkn2, Cell division protein kinase 2, Cyclin-dependent kinase 2
 
 
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Disease relevance of Cdk2

  • Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma cells [1].
  • METHODS: Rats with experimentally induced gastric ulcers were treated twice daily for 14 days either with sulglycotide at 200 mg/kg or vehicle, and at different stages of the treatment their stomachs were used for macroscopic damage assessment and quantitation of gastric mucosal Cdk2 and PCNA expression [2].
  • Constitutive overexpression of CDK2 inhibits neuronal differentiation of rat pheochromocytoma PC12 cells [3].
  • We conclude that reducing the activity of CDK2 with Roscovitine in experimental glomerulonephritis decreases cell proliferation and matrix production, resulting in improved renal function, and may be a useful therapeutic intervention in disease characterized by proliferation [4].
 

High impact information on Cdk2

  • These results indicate that downregulation of cyclin-E/Cdk2 kinase activity following the G1/S-phase transition may be necessary for the maintenance of karyotypic stability [5].
  • C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4 [6].
  • Our results show that a new biological function for the CDK inhibitor p27 is protection of cells from apoptosis by constraining CDK2 activity [7].
  • Ectopic overexpression of p27 in serum-stimulated VSMCs resulted in the inhibition of cdk2 activity and repression of cyclin A promoter activity [8].
  • Thus, the inhibition of cdk2 function and repression of cyclin A gene transcription through the induction of the endogenous p27 protein provides a mechanism for the inhibition of VSMC growth at late time points after angioplasty [8].
 

Chemical compound and disease context of Cdk2

  • 2. Rats with experimentally induced gastric ulcers were treated twice daily for 14 days with either ebrotidine at 100 mg/kg, sucralfate at 100 mg/kg or vehicle, and at different stages of treatment their stomachs were used for quantitization of gastric mucosal PCNA and Cdk2 expression [9].
 

Biological context of Cdk2

  • Cdk2-dependent phosphorylation therefore provides a switch during late G1-to-S phase that both nullifies an early G1 cell cycle regulatory function of Id3 and modulates its target bHLH specificity [10].
  • In summary, E1A binding to pocket proteins has effects beyond those produced by E2F-1 alone and can drive S-phase entry that is resistant to p21 and independent of an increase in Cdk2 function [11].
  • These data also demonstrate that the ability of Id3 to promote cell cycle S phase entry is not simply a function of its ability to modulate bHLH heterodimer-dependent gene expression and establish a biologically important mechanism through which Cdk2 and Id-bHLH functions are integrated in the coordination of cell proliferation and differentiation [10].
  • Thus, E1A can cause G1 exit without an increase in Cdk2 activity, if the pocket protein-binding domain is intact [11].
  • Nitric oxide-induced downregulation of Cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells [12].
 

Anatomical context of Cdk2

  • Thus, E2F-1-induced Cdk2 function was necessary, although not sufficient, to trigger DNA synthesis in cardiac muscle cells [11].
  • These data indicate that geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E expression, Cdk2 activation, and G1/S transition in rat astrocytes [13].
  • Screening of Golgi, endosomes (ENs), plasmalemma (PM), and cytosolic (Cyt) fractions revealed the presence of the mitotic kinase Cdk2 in ENs, PM, and Cyt [14].
  • Here we show that cyclin E mutants defective to form an active kinase complex with Cdk2 are unable to drive cells from G(1) into S phase but can still malignantly transform rat embryo fibroblasts in cooperation with Ha-Ras [15].
  • Characterization of Cdk2-cyclin E complexes in plasma membrane and endosomes of liver parenchyma. Insulin-dependent regulation [14].
 

Associations of Cdk2 with chemical compounds

 

Physical interactions of Cdk2

  • Activation of the cyclin E/Cdk2 complex may play an important role in mid-G1/S-phase progression in proliferating mammalian cells [18].
  • On the other hand, levels of mucosal p21(Waf1/Cip1) (total and the fraction bound to Cdk2), one of the universal inhibitors of Cdks, were found to be lower in aged than in young rats [19].
 

Regulatory relationships of Cdk2

  • Forced expression of cyclin E induced endogenous Cdk2 activity but not G1 exit [11].
  • In young cells, prior treatment with rapamycin inhibited the induction of DNA synthesis and activation of CDK2 to levels similar to those seen in aged cells without inhibiting ERK activity and cyclin D1 expression [20].
  • Previous studies concluded that FB1 repressed cyclin-dependent kinase 2 (CDK2) activity but induced CDK inhibitors p21(Waf1/Cip1), p27(Kip1), and p57(Kip2) in monkey kidney cells (CV-1) [21].
 

Other interactions of Cdk2

  • Our results demonstrate similarities between the activation mechanisms of ERK2 and the cell cycle control enzyme, Cdk2 (cyclin-dependent kinase 2) [22].
  • As CycE/Cdk2 activity is essential for G1/S transition, we have investigated the mechanism by which Myc can activiate CycE/Cdk2 [23].
  • Regulation of Cdk4, cyclin E and Cdk2 protein levels was also not different [24].
  • In the lens epithelium, we detected proteins and mRNAs corresponding to all other Cdks examined (Cdk2, Cdk4, Cdk7, Cdk8) throughout this developmental period [25].
  • In contrast, ATRA strongly suppressed the pRb kinase activities of the cyclin-dependent kinases (Cdks) Cdk4, Cdk6, and Cdk2 [26].
 

Analytical, diagnostic and therapeutic context of Cdk2

  • Partial proteolytic mapping showed that Cdk2-beta gene product is 39 kDa Cdk2 in the immunoblotting [27].
  • Northern blot analysis indicated that the sizes of rat Cdk2-alpha and -beta mRNAs are approximately 2.5 kb and 3.0 kb, respectively [27].
  • Interestingly, immunoprecipitation experiments provided evidence that the decreased levels of p21(CIP1) were associated with a reduced interaction of this CKI with cyclin E-Cdk2 complexes [28].
  • We evaluated the effect of targeted inhibition of Cdk2 activity by CYC202 (R-roscovitine) on hepatocytes proliferation in vivo after 70% partial hepatectomy (PH) in rats [18].
  • METHODS: Protein expression of the cyclins (D-type and E), Cdks (Cdk2 and 4), and Cdk inhibitors (p21 and p27) was measured by Western blot after SHAM operation or PH in F344 rats [29].

References

  1. Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma cells. Choi, K.S., Eom, Y.W., Kang, Y., Ha, M.J., Rhee, H., Yoon, J.W., Kim, S.J. J. Biol. Chem. (1999) [Pubmed]
  2. Gastric mucosal cell cycle regulation with ulcer healing by sulglycotide. Slomiany, B.L., Piotrowski, J., Slomiany, A. Scand. J. Gastroenterol. (1997) [Pubmed]
  3. Constitutive overexpression of CDK2 inhibits neuronal differentiation of rat pheochromocytoma PC12 cells. Dobashi, Y., Kudoh, T., Matsumine, A., Toyoshima, K., Akiyama, T. J. Biol. Chem. (1995) [Pubmed]
  4. Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist. Pippin, J.W., Qu, Q., Meijer, L., Shankland, S.J. J. Clin. Invest. (1997) [Pubmed]
  5. Deregulated cyclin E induces chromosome instability. Spruck, C.H., Won, K.A., Reed, S.I. Nature (1999) [Pubmed]
  6. C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Wang, H., Iakova, P., Wilde, M., Welm, A., Goode, T., Roesler, W.J., Timchenko, N.A. Mol. Cell (2001) [Pubmed]
  7. Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1). Hiromura, K., Pippin, J.W., Fero, M.L., Roberts, J.M., Shankland, S.J. J. Clin. Invest. (1999) [Pubmed]
  8. Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27(KIP1), an inhibitor of neointima formation in the rat carotid artery. Chen, D., Krasinski, K., Sylvester, A., Chen, J., Nisen, P.D., Andrés, V. J. Clin. Invest. (1997) [Pubmed]
  9. Cell cycle progression during gastric ulcer healing by ebrotidine and sucralfate. Slomiany, B.L., Piotrowski, J., Slomiany, A. Gen. Pharmacol. (1997) [Pubmed]
  10. Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation. Deed, R.W., Hara, E., Atherton, G.T., Peters, G., Norton, J.D. Mol. Cell. Biol. (1997) [Pubmed]
  11. E1A can provoke G1 exit that is refractory to p21 and independent of activating cdk2. Akli, S., Zhan, S., Abdellatif, M., Schneider, M.D. Circ. Res. (1999) [Pubmed]
  12. Nitric oxide-induced downregulation of Cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells. Guo, K., Andrés, V., Walsh, K. Circulation (1998) [Pubmed]
  13. Activation of cyclin-dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes. Geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E gene expression. Tanaka, T., Tatsuno, I., Noguchi, Y., Uchida, D., Oeda, T., Narumiya, S., Yasuda, T., Higashi, H., Kitagawa, M., Nakayama, K., Saito, Y., Hirai, A. J. Biol. Chem. (1998) [Pubmed]
  14. Characterization of Cdk2-cyclin E complexes in plasma membrane and endosomes of liver parenchyma. Insulin-dependent regulation. Gaulin, J.F., Fiset, A., Fortier, S., Faure, R.L. J. Biol. Chem. (2000) [Pubmed]
  15. The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein. Geisen, C., Moroy, T. J. Biol. Chem. (2002) [Pubmed]
  16. Differential regulation of p27(Kip1) expression by mitogenic and hypertrophic factors: Involvement of transcriptional and posttranscriptional mechanisms. Servant, M.J., Coulombe, P., Turgeon, B., Meloche, S. J. Cell Biol. (2000) [Pubmed]
  17. Ectopic expression of Cdc25A accelerates the G(1)/S transition and leads to premature activation of cyclin E- and cyclin A-dependent kinases. Blomberg, I., Hoffmann, I. Mol. Cell. Biol. (1999) [Pubmed]
  18. Blunted DNA synthesis and delayed S-phase entry following inhibition of Cdk2 activity in the regenerating rat liver. Stärkel, P., De Saeger, C., Sempoux, C., Legrand, E., Leclercq, I., Horsmans, Y. Lab. Invest. (2005) [Pubmed]
  19. Aging enhances G(1) phase in the colonic mucosa of rats. Xiao, Z.Q., Jaszewski, R., Majumdar, A.P. Mech. Ageing Dev. (2000) [Pubmed]
  20. Impairments in both p70 S6 kinase and extracellular signal-regulated kinase signaling pathways contribute to the decline in proliferative capacity of aged hepatocytes. Liu, Y., Gorospe, M., Kokkonen, G.C., Boluyt, M.O., Younes, A., Mock, Y.D., Wang, X., Roth, G.S., Holbrook, N.J. Exp. Cell Res. (1998) [Pubmed]
  21. The mycotoxin fumonisin B1 transcriptionally activates the p21 promoter through a cis-acting element containing two Sp1 binding sites. Zhang, Y., Dickman, M.B., Jones, C. J. Biol. Chem. (1999) [Pubmed]
  22. Mechanism of activation of ERK2 by dual phosphorylation. Prowse, C.N., Lew, J. J. Biol. Chem. (2001) [Pubmed]
  23. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27(Kip1) binding to newly formed complexes. Pérez-Roger, I., Solomon, D.L., Sewing, A., Land, H. Oncogene (1997) [Pubmed]
  24. Mechanisms underlying maintenance of smooth muscle cell quiescence in rat aorta: role of the cyclin dependent kinases and their inhibitors. Izzard, T.D., Taylor, C., Birkett, S.D., Jackson, C.L., Newby, A.C. Cardiovasc. Res. (2002) [Pubmed]
  25. Changes in cyclin dependent kinase expression and activity accompanying lens fiber cell differentiation. Gao, C.Y., Rampalli, A.M., Cai, H.C., He, H.Y., Zelenka, P.S. Exp. Eye Res. (1999) [Pubmed]
  26. All-trans retinoic acid inhibits vascular smooth muscle cell proliferation targeting multiple genes for cyclins and cyclin-dependent kinases. Kosaka, C., Sasaguri, T., Komiyama, Y., Takahashi, H. Hypertens. Res. (2001) [Pubmed]
  27. A variant form of cyclin-dependent kinase 2 (Cdk2) in a malignantly transformed rat thyroid (FRTL-Tc) cell line. Kotani, S., Endo, T., Kitagawa, M., Higashi, H., Onaya, T. Oncogene (1995) [Pubmed]
  28. Retinoic acid-induced proliferation of lung alveolar epithelial cells is linked to p21(CIP1) downregulation. Nabeyrat, E., Corroyer, S., Epaud, R., Besnard, V., Cazals, V., Clement, A. Am. J. Physiol. Lung Cell Mol. Physiol. (2000) [Pubmed]
  29. Cell cycle-mediated regulation of hepatic regeneration. Ehrenfried, J.A., Ko, T.C., Thompson, E.A., Evers, B.M. Surgery (1997) [Pubmed]
 
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