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Gene Review

CCNE1  -  cyclin E1

Homo sapiens

Synonyms: CCNE, G1/S-specific cyclin-E1
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Disease relevance of CCNE1


Psychiatry related information on CCNE1

  • After a long latency period of over 200 days, these animals develop spontaneous monoclonal T cell lymphoma whereas none of the single CD2-cyclin E transgenic or the p27(Kip1)-deficient mice showed any sign of lymphoid malignancies [7].

High impact information on CCNE1

  • Paradoxically, under certain circumstances, CDKs such as cyclin E-cdk2 are also required to promote licensing [8].
  • This novel mechanism for regulating protein stability establishes a window of time prior to S phase when pre-RCs can assemble which we propose represents a critical function of cyclin E [8].
  • OCA-S also interacts with NPAT, a cyclin E/cdk2 substrate that is broadly involved in histone gene transcription [9].
  • Cell proliferation without cyclin E-CDK2 [10].
  • In postmitotic mutant cells, levels of Cyclin E and Cyclin A are elevated [11].

Chemical compound and disease context of CCNE1


Biological context of CCNE1

  • Accordingly, CARM1-deficient cells lack these modifications and present lowered levels and altered kinetics of CCNE1 and DHFR mRNA expression [1].
  • E2F-dependent regulation of the CCNE1 promoter was shown to correlate with changes in the level of H3-K9 acetylation/methylation of nucleosomal histones positioned at the transcriptional start site region [1].
  • Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in fallopian tube carcinoma [17].
  • However, in many human tumours cyclin E is overexpressed and the levels of protein and kinase activity are often deregulated relative to the cell cycle [18].
  • Deregulated cyclin E induces chromosome instability [18].

Anatomical context of CCNE1


Associations of CCNE1 with chemical compounds

  • Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution [12].
  • Ectopic expression of cyclin D1 in progestin-inhibited cells led to the reappearance of the 120-kDa active form of cyclin E-Cdk2 preceding the resumption of cell cycle progression [22].
  • The p18-cyclin E expression was prevented by Bcl-2 overexpression and by the general caspase and specific caspase 3 pharmacologic inhibitors zVAD-fluoromethyl ketone (zVAD-fmk) and N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), indicating that it was linked to apoptosis [23].
  • Overexpression of cyclin E(276-395), but not of several other cyclin E mutants, specifically induced phosphatidylserine exposure and caspase activation in a dose-dependent manner, which were inhibited in Bcl-2-overexpressing cells or in the presence of zVAD-fmk [23].
  • Mutation of Thr(62) to alanine led to a dramatic reduction in the extent of Thr(380) phosphorylation, suggesting an indirect effect of this mutation on cyclin E turnover [24].

Physical interactions of CCNE1

  • Furthermore, another p27 mutant [p27(CK-)] that can be phosphorylated by cyclin E/Cdk2 but cannot bind this kinase complex, is refractory to ubiquitination [25].
  • This cyclin E/E2F complex was seen in a variety of human cell lines from various tissues, but its appearance was detected primarily during the G1 phase of the cell cycle [26].
  • In vitro, SKP2 specifically interacted with the cyclin E peptide containing the phosphorylated-Thr380 but not with a cognate nonphosphorylated peptide [27].
  • In investigating the mechanism by which pRb induces senescence, we have found that pRb causes a posttranscriptional accumulation of the cyclin-dependent kinase inhibitor p27(KIP1) that is accompanied by an increase in p27(KIP1) specifically bound to cyclin E and a concomitant decrease in cyclin E-associated kinase activity [28].
  • We find that cyclin E binds the NH(2)-terminal region of Cdc6 containing Cy--Arg-X-Leu (RXL) motifs [29].
  • Structures of the Skp1-Fbw7 complex bound to cyclin E peptides identify a doubly phosphorylated pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron and a singly phosphorylated pThr62 motif as a low-affinity one [30].

Enzymatic interactions of CCNE1


Regulatory relationships of CCNE1


Other interactions of CCNE1

  • Cyclin E-associated kinase activity was correlated with the appearance of complexes containing cyclin E and the cyclin-dependent kinase Cdk2 [36].
  • We report here that cyclin E is found associated with the transcription factor E2F in a temporally regulated fashion [26].
  • Cyclin E is classified as a putative G1 cyclin on the basis of its cyclic pattern of mRNA expression, with maximal levels being detected near the G1/S boundary [26].
  • These results suggest a function for Xic-1 in the control of DNA synthesis by cyclin E/Cdk2 [37].
  • Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb [3].

Analytical, diagnostic and therapeutic context of CCNE1


  1. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. El Messaoudi, S., Fabbrizio, E., Rodriguez, C., Chuchana, P., Fauquier, L., Cheng, D., Theillet, C., Vandel, L., Bedford, M.T., Sardet, C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Analysis of gene amplification and prognostic markers in ovarian cancer using comparative genomic hybridization for microarrays and immunohistochemical analysis for tissue microarrays. Mayr, D., Kanitz, V., Anderegg, B., Luthardt, B., Engel, J., Löhrs, U., Amann, G., Diebold, J. Am. J. Clin. Pathol. (2006) [Pubmed]
  3. Cyclin E, a redundant cyclin in breast cancer. Gray-Bablin, J., Zalvide, J., Fox, M.P., Knickerbocker, C.J., DeCaprio, J.A., Keyomarsi, K. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  4. Cyclin E is the only cyclin-dependent kinase 2-associated cyclin that predicts metastasis and survival in early stage non-small cell lung cancer. Müller-Tidow, C., Metzger, R., Kügler, K., Diederichs, S., Idos, G., Thomas, M., Dockhorn-Dworniczak, B., Schneider, P.M., Koeffler, H.P., Berdel, W.E., Serve, H. Cancer Res. (2001) [Pubmed]
  5. Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. Takano, Y., Kato, Y., van Diest, P.J., Masuda, M., Mitomi, H., Okayasu, I. Am. J. Pathol. (2000) [Pubmed]
  6. Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors. Grabowski, P., Schrader, J., Wagner, J., Hörsch, D., Arnold, R., Arnold, C.N., Georgieva, I., Stein, H., Zeitz, M., Daniel, P.T., Sturm, I. Clin. Cancer Res. (2008) [Pubmed]
  7. Loss of p27(Kip1) cooperates with cyclin E in T-cell lymphomagenesis. Geisen, C., Karsunky, H., Yücel, R., Möröy, T. Oncogene (2003) [Pubmed]
  8. 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]
  9. S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Zheng, L., Roeder, R.G., Luo, Y. Cell (2003) [Pubmed]
  10. Cell proliferation without cyclin E-CDK2. Méndez, J. Cell (2003) [Pubmed]
  11. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Tapon, N., Ito, N., Dickson, B.J., Treisman, J.E., Hariharan, I.K. Cell (2001) [Pubmed]
  12. Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Planas-Silva, M.D., Weinberg, R.A. Mol. Cell. Biol. (1997) [Pubmed]
  13. A pure estrogen antagonist inhibits cyclin E-Cdk2 activity in MCF-7 breast cancer cells and induces accumulation of p130-E2F4 complexes characteristic of quiescence. Carroll, J.S., Prall, O.W., Musgrove, E.A., Sutherland, R.L. J. Biol. Chem. (2000) [Pubmed]
  14. Protein levels of p21, p27, cyclin E and Bax predict sensitivity to cisplatin and paclitaxel in head and neck squamous cell carcinomas. Taguchi, T., Kato, Y., Baba, Y., Nishimura, G., Tanigaki, Y., Horiuchi, C., Mochimatsu, I., Tsukuda, M. Oncol. Rep. (2004) [Pubmed]
  15. Cyclin D1 overexpression induces progestin resistance in T-47D breast cancer cells despite p27(Kip1) association with cyclin E-Cdk2. Musgrove, E.A., Hunter, L.J., Lee, C.S., Swarbrick, A., Hui, R., Sutherland, R.L. J. Biol. Chem. (2001) [Pubmed]
  16. Increased p21 expression and complex formation with cyclin E/CDK2 in retinoid-induced pre-B lymphoma cell apoptosis. Bao, G.C., Wang, J.G., Jong, A. FEBS Lett. (2006) [Pubmed]
  17. Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in fallopian tube carcinoma. Snijders, A.M., Nowee, M.E., Fridlyand, J., Piek, J.M., Dorsman, J.C., Jain, A.N., Pinkel, D., van Diest, P.J., Verheijen, R.H., Albertson, D.G. Oncogene (2003) [Pubmed]
  18. Deregulated cyclin E induces chromosome instability. Spruck, C.H., Won, K.A., Reed, S.I. Nature (1999) [Pubmed]
  19. TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas. Yasui, K., Arii, S., Zhao, C., Imoto, I., Ueda, M., Nagai, H., Emi, M., Inazawa, J. Hepatology (2002) [Pubmed]
  20. Maturation of human cyclin E requires the function of eukaryotic chaperonin CCT. Won, K.A., Schumacher, R.J., Farr, G.W., Horwich, A.L., Reed, S.I. Mol. Cell. Biol. (1998) [Pubmed]
  21. Temporally and spatially coordinated expression of cell cycle regulatory factors after angioplasty. Wei, G.L., Krasinski, K., Kearney, M., Isner, J.M., Walsh, K., Andrés, V. Circ. Res. (1997) [Pubmed]
  22. Mechanisms of cyclin-dependent kinase inactivation by progestins. Musgrove, E.A., Swarbrick, A., Lee, C.S., Cornish, A.L., Sutherland, R.L. Mol. Cell. Biol. (1998) [Pubmed]
  23. Proteolytic cleavage of cyclin E leads to inactivation of associated kinase activity and amplification of apoptosis in hematopoietic cells. Mazumder, S., Gong, B., Chen, Q., Drazba, J.A., Buchsbaum, J.C., Almasan, A. Mol. Cell. Biol. (2002) [Pubmed]
  24. Recognition of phosphodegron motifs in human cyclin E by the SCF(Fbw7) ubiquitin ligase. Ye, X., Nalepa, G., Welcker, M., Kessler, B.M., Spooner, E., Qin, J., Elledge, S.J., Clurman, B.E., Harper, J.W. J. Biol. Chem. (2004) [Pubmed]
  25. 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]
  26. Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Lees, E., Faha, B., Dulic, V., Reed, S.I., Harlow, E. Genes Dev. (1992) [Pubmed]
  27. The F-box protein SKP2 binds to the phosphorylated threonine 380 in cyclin E and regulates ubiquitin-dependent degradation of cyclin E. Yeh, K.H., Kondo, T., Zheng, J., Tsvetkov, L.M., Blair, J., Zhang, H. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  28. Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Alexander, K., Hinds, P.W. Mol. Cell. Biol. (2001) [Pubmed]
  29. Cyclin E uses Cdc6 as a chromatin-associated receptor required for DNA replication. Furstenthal, L., Kaiser, B.K., Swanson, C., Jackson, P.K. J. Cell Biol. (2001) [Pubmed]
  30. Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Hao, B., Oehlmann, S., Sowa, M.E., Harper, J.W., Pavletich, N.P. Mol. Cell (2007) [Pubmed]
  31. Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression. Keenan, S.M., Lents, N.H., Baldassare, J.J. J. Biol. Chem. (2004) [Pubmed]
  32. The unfolded protein response affects neuronal cell cycle protein expression: Implications for Alzheimer's disease pathogenesis. Hoozemans, J.J., Stieler, J., van Haastert, E.S., Veerhuis, R., Rozemuller, A.J., Baas, F., Eikelenboom, P., Arendt, T., Scheper, W. Exp. Gerontol. (2006) [Pubmed]
  33. Activation of cyclin-dependent kinase 2 by full length and low molecular weight forms of cyclin E in breast cancer cells. Harwell, R.M., Mull, B.B., Porter, D.C., Keyomarsi, K. J. Biol. Chem. (2004) [Pubmed]
  34. MYC can enforce cell cycle transit from G1 to S and G2 to S, but not mitotic cellular division, independent of p27-mediated inihibition of cyclin E/CDK2. Deb-Basu, D., Karlsson, A., Li, Q., Dang, C.V., Felsher, D.W. Cell Cycle (2006) [Pubmed]
  35. Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor cells. Li, X., Tanaka, K., Nakatani, F., Matsunobu, T., Sakimura, R., Hanada, M., Okada, T., Nakamura, T., Iwamoto, Y. Int. J. Cancer (2005) [Pubmed]
  36. Association of human cyclin E with a periodic G1-S phase protein kinase. Dulić, V., Lees, E., Reed, S.I. Science (1992) [Pubmed]
  37. Cloning and characterization of the Xenopus cyclin-dependent kinase inhibitor p27XIC1. Su, J.Y., Rempel, R.E., Erikson, E., Maller, J.L. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  38. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Ohtsubo, M., Theodoras, A.M., Schumacher, J., Roberts, J.M., Pagano, M. Mol. Cell. Biol. (1995) [Pubmed]
  39. Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence. Ito, Y., Matsuura, N., Sakon, M., Miyoshi, E., Noda, K., Takeda, T., Umeshita, K., Nagano, H., Nakamori, S., Dono, K., Tsujimoto, M., Nakahara, M., Nakao, K., Taniguchi, N., Monden, M. Hepatology (1999) [Pubmed]
  40. 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]
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