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Gene Review

Ccne1  -  cyclin E1

Mus musculus

Synonyms: AW538188, Ccne, CycE1, G1/S-specific cyclin-E1, cyclin E
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Disease relevance of Ccne1

  • We show that expression of new cyclin E1 mRNA variants IN3, Delta4, and Delta5 is associated with retarded proliferation in murine hepatocellular carcinoma [1].
  • These findings demonstrate that high level expression of cyclin E can predispose T-cells for hyperplasia and malignant transformation [2].
  • When treated with the DNA methylating carcinogen N-methylnitrosourea (MNU) that provokes the development of T-cell lymphomas, CD2-cyclin E transgenic animals came down with T-cell neoplasia showing a significant higher incidence (54%) than normal non transgenic controls (31%) [2].
  • Our group recently reported that overexpression and generation of low-molecular-weight (LMW) isoforms of cyclin E were associated with poor clinical outcome among breast cancer patients [3].
  • In rats the development of hypertrophy was associated with an increase in cdk4/cyclin D kinase at days 4, 7, and 10, and an increase in cdk2/cyclin E kinase activity at days 2, 4, and 7 [4].
  • Both primary mammary tumor formation and metastasis were markedly enhanced in LMW cyclin E transgenic mice [5].

Psychiatry related information on Ccne1


High impact information on Ccne1

  • These findings define a molecular function for E type cyclins in cell cycle reentry and reveal a differential requirement for cyclin E in normal versus oncogenic proliferation [7].
  • Molecular analyses revealed that cells lacking cyclin E fail to normally incorporate MCM proteins into DNA replication origins during G(0)-->S progression [7].
  • However, endoreplication of trophoblast giant cells and megakaryocytes is severely impaired in the absence of cyclin E. Cyclin E-deficient cells proliferate actively under conditions of continuous cell cycling but are unable to reenter the cell cycle from the quiescent G(0) state [7].
  • Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication [8].
  • In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity [9].

Chemical compound and disease context of Ccne1


Biological context of Ccne1


Anatomical context of Ccne1

  • Additionally, we demonstrate that a new cyclin E1 isoform Delta3/8 lacking the central part of wild-type mRNA is expressed predominantly in nonproliferating murine hepatocytes [1].
  • Cyclin E1 controls G1/S phase transition of the eukaryotic cell cycle [1].
  • Finally, the level of PCR products for cyclin E and cdk2 gradually decreased during the progression from meiotically incompetent oocytes to metaphase II-arrested eggs [19].
  • We determined the acetylation level of individual nucleosomes present in the cyclin E promoter of RB(+/+) and RB(-/-) mouse embryo fibroblasts [20].
  • Interestingly, IL-4, which by itself does not stimulate proliferation of immature B cells, induced expression of cyclin E and cdk2 [21].

Associations of Ccne1 with chemical compounds

  • However, both LIF and PGF2alpha increase cyclin E expression [22].
  • We now show that cyclin E/cdk2 phosphorylates p27 at a carboxy-terminal threonine residue (T187) in vitro; mutation of this residue to valine stabilises cyclin E/cdk2 complexes [23].
  • Whereas cyclin E overexpression alone did not lead to an increased CDK2 activity we observed in all tumors that emerged from either MNU treated normal mice or treated CD2-cyclin E transgenics a downregulation of p27KIP1 and a higher histone H1 kinase activity in CDK2 immunoprecipitates compared to normal tissue [2].
  • However, by 72 h, the cyclin E overexpressors rounded up but remained attached to the substratum, indicating a delayed response to lovastatin [24].
  • In addition, 24 h of cycloheximide treatment caused depletion of RhoA from the membrane (active) fraction in neo cells, but in the cells overexpressing cyclin E, RhoA remained in the active (membrane-associated) fraction [24].

Physical interactions of Ccne1

  • Immunoprecipitates of cyclin E1 complexes from Cdk2(-/-) spleen extracts displayed no activity toward histone H1 [25].
  • Finally we found that the lack of kinase activity associated with cyclin E/cdk2 complexes was correlated with increased amounts of cdk2- and cyclin E-bound p27 [26].
  • Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro [27].
  • Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation [28].

Enzymatic interactions of Ccne1


Regulatory relationships of Ccne1

  • Cdc42V12 promotes Cdk2 activation by selectively inducing cyclin E expression without affecting other regulatory proteins such as the p27 Cdk inhibitor or Cdc25A [18].
  • In addition, cyclin E binds to and activates Cdc2 [14].
  • In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3 [29].
  • We found that pRb represses the cyclin E promoter through histone deacetylation of a single nucleosome, to which it and histone deacetylase 1 bind [20].
  • These results suggest that c-myc may be a component of the signaling pathway that induces cyclin E and cdk2 expression [21].

Other interactions of Ccne1


Analytical, diagnostic and therapeutic context of Ccne1

  • Cyclin E-p27 opposition and regulation of the G1 phase of the cell cycle in the murine neocortical PVE: a quantitative analysis of mRNA in situ hybridization [33].
  • Accelerated S-phase entry by proliferating R2LivKO hepatocytes coincided with the hyperphosphorylation of Rb protein and the early upregulation of cyclin D1 and cyclin E. However, by 120 hours after partial hepatectomy, hepatocyte proliferation was back to baseline in both control and R2LivKO liver [34].
  • Screening by cDNA microarray showed that PPARgamma ligand treatment was associated with upregulation of bad and p53, and downregulation of bcl-2, bcl-xl, and cyclin E1 in MKN45 cells, which was confirmed by quantitative real time PCR [35].
  • Subcellular cell fractionation experiments revealed that the complex with cyclin E is formed mostly in the nuclear fractions, although in these cells PKCeta is predominantly expressed in the cytosolic fractions [36].
  • Immunofluorescence staining demonstrated that in serum-starved cells PKCeta is concentrated at the perinuclear zone, which is also the site of its colocalization with cyclin E. Colocalization of PKCeta and cyclin E in the perinuclear region was observed in serum-starved cells, and less in proliferating cells [36].


  1. Expression of a cyclin E1 isoform in mice is correlated with the quiescent cell cycle status of hepatocytes in vivo. Zschemisch, N.H., Liedtke, C., Dierssen, U., Nevzorova, Y.A., Wüstefeld, T., Borlak, J., Manns, M.P., Trautwein, C. Hepatology (2006) [Pubmed]
  2. Oncogenic potential of cyclin E in T-cell lymphomagenesis in transgenic mice: evidence for cooperation between cyclin E and Ras but not Myc. Karsunky, H., Geisen, C., Schmidt, T., Haas, K., Zevnik, B., Gau, E., Möröy, T. Oncogene (1999) [Pubmed]
  3. Low-molecular-weight cyclin E: the missing link between biology and clinical outcome. Akli, S., Keyomarsi, K. Breast Cancer Res. (2004) [Pubmed]
  4. Compensatory renal hypertrophy is mediated by a cell cycle-dependent mechanism. Liu, B., Preisig, P.A. Kidney Int. (2002) [Pubmed]
  5. Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway. Akli, S., Van Pelt, C.S., Bui, T., Multani, A.S., Chang, S., Johnson, D., Tucker, S., Keyomarsi, K. Cancer Res. (2007) [Pubmed]
  6. Cyclin A activates the DNA polymerase delta -dependent elongation machinery in vitro: A parvovirus DNA replication model. Bashir, T., Horlein, R., Rommelaere, J., Willwand, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  7. Cyclin E ablation in the mouse. Geng, Y., Yu, Q., Sicinska, E., Das, M., Schneider, J.E., Bhattacharya, S., Rideout, W.M., Bronson, R.T., Gardner, H., Sicinski, P. Cell (2003) [Pubmed]
  8. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Okuda, M., Horn, H.F., Tarapore, P., Tokuyama, Y., Smulian, A.G., Chan, P.K., Knudsen, E.S., Hofmann, I.A., Snyder, J.D., Bove, K.E., Fukasawa, K. Cell (2000) [Pubmed]
  9. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Hakem, R., de la Pompa, J.L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., Firpo, E., Hui, C.C., Roberts, J., Rossant, J., Mak, T.W. Cell (1996) [Pubmed]
  10. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Chen, Y., Tseng, S.H., Lai, H.S., Chen, W.J. Surgery (2004) [Pubmed]
  11. Cyclin E both regulates and is regulated by calpain 2, a protease associated with metastatic breast cancer phenotype. Libertini, S.J., Robinson, B.S., Dhillon, N.K., Glick, D., George, M., Dandekar, S., Gregg, J.P., Sawai, E., Mudryj, M. Cancer Res. (2005) [Pubmed]
  12. Troglitazone induces p27Kip1-associated cell-cycle arrest through down-regulating Skp2 in human hepatoma cells. Koga, H., Harada, M., Ohtsubo, M., Shishido, S., Kumemura, H., Hanada, S., Taniguchi, E., Yamashita, K., Kumashiro, R., Ueno, T., Sata, M. Hepatology (2003) [Pubmed]
  13. Inhibition of E2F abrogates the development of cardiac myocyte hypertrophy. Vara, D., Bicknell, K.A., Coxon, C.H., Brooks, G. J. Biol. Chem. (2003) [Pubmed]
  14. Cdc2-cyclin E complexes regulate the G1/S phase transition. Aleem, E., Kiyokawa, H., Kaldis, P. Nat. Cell Biol. (2005) [Pubmed]
  15. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. Macleod, K.F., Hu, Y., Jacks, T. EMBO J. (1996) [Pubmed]
  16. Dna damage-induced G(1) arrest in hematopoietic cells is overridden following phosphatidylinositol 3-kinase-dependent activation of cyclin-dependent kinase 2. Eapen, A.K., Henry, M.K., Quelle, D.E., Quelle, F.W. Mol. Cell. Biol. (2001) [Pubmed]
  17. Mad1 function in cell proliferation and transcriptional repression is antagonized by cyclin E/CDK2. Rottmann, S., Menkel, A.R., Bouchard, C., Mertsching, J., Loidl, P., Kremmer, E., Eilers, M., Lüscher-Firzlaff, J., Lilischkis, R., Lüscher, B. J. Biol. Chem. (2005) [Pubmed]
  18. Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression. Chou, M.M., Masuda-Robens, J.M., Gupta, M.L. J. Biol. Chem. (2003) [Pubmed]
  19. Temporal patterns of gene expression of G1-S cyclins and cdks during the first and second mitotic cell cycles in mouse embryos. Moore, G.D., Ayabe, T., Kopf, G.S., Schultz, R.M. Mol. Reprod. Dev. (1996) [Pubmed]
  20. Retinoblastoma protein transcriptional repression through histone deacetylation of a single nucleosome. Morrison, A.J., Sardet, C., Herrera, R.E. Mol. Cell. Biol. (2002) [Pubmed]
  21. Immature stage B cells enter but do not progress beyond the early G1 phase of the cell cycle in response to antigen receptor signaling. Carman, J.A., Wechsler-Reya, R.J., Monroe, J.G. J. Immunol. (1996) [Pubmed]
  22. Leukemia inhibitory factor induces DNA synthesis in Swiss mouse 3T3 cells independently of cyclin D1 expression through a mechanism involving MEK/ERK1/2 activation. Dekanty, A., Sauane, M., Cadenas, B., Coluccio, F., Barrio, M., Casala, J., Paciencia, M., Rogers, F., Coso, O.A., Piwien-Pilipuk, G., Rudland, P.S., de Asúa, L.J. J. Biol. Chem. (2006) [Pubmed]
  23. Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes. Müller, D., Bouchard, C., Rudolph, B., Steiner, P., Stuckmann, I., Saffrich, R., Ansorge, W., Huttner, W., Eilers, M. Oncogene (1997) [Pubmed]
  24. Effect of cyclin E overexpression on lovastatin-induced G1 arrest and RhoA inactivation in NIH3T3 cells. Ghosh, P.M., Moyer, M.L., Mott, G.E., Kreisberg, J.I. J. Cell. Biochem. (1999) [Pubmed]
  25. Cdk2 knockout mice are viable. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L., Kaldis, P. Curr. Biol. (2003) [Pubmed]
  26. Effect of TGF-beta1 on cell cycle regulatory proteins in LPS-stimulated normal mouse B lymphocytes. Bouchard, C., Fridman, W.H., Sautès, C. J. Immunol. (1997) [Pubmed]
  27. Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. Nakayama, K., Nagahama, H., Minamishima, Y.A., Matsumoto, M., Nakamichi, I., Kitagawa, K., Shirane, M., Tsunematsu, R., Tsukiyama, T., Ishida, N., Kitagawa, M., Nakayama, K., Hatakeyama, S. EMBO J. (2000) [Pubmed]
  28. Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Clurman, B.E., Sheaff, R.J., Thress, K., Groudine, M., Roberts, J.M. Genes Dev. (1996) [Pubmed]
  29. A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1). Alevizopoulos, K., Catarin, B., Vlach, J., Amati, B. EMBO J. (1998) [Pubmed]
  30. Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. Alevizopoulos, K., Vlach, J., Hennecke, S., Amati, B. EMBO J. (1997) [Pubmed]
  31. Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice. Tong, W., Pollard, J.W. Mol. Cell. Biol. (2001) [Pubmed]
  32. Neoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesis. Yamamoto, M., Tamakawa, S., Yoshie, M., Yaginuma, Y., Ogawa, K. Mol. Carcinog. (2006) [Pubmed]
  33. Cyclin E-p27 opposition and regulation of the G1 phase of the cell cycle in the murine neocortical PVE: a quantitative analysis of mRNA in situ hybridization. Delalle, I., Takahashi, T., Nowakowski, R.S., Tsai, L.H., Caviness, V.S. Cereb. Cortex (1999) [Pubmed]
  34. Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice. Oe, S., Lemmer, E.R., Conner, E.A., Factor, V.M., Levéen, P., Larsson, J., Karlsson, S., Thorgeirsson, S.S. Hepatology (2004) [Pubmed]
  35. Effect of peroxisome proliferator activated receptor gamma ligands on growth and gene expression profiles of gastric cancer cells. Leung, W.K., Bai, A.H., Chan, V.Y., Yu, J., Chan, M.W., To, K.F., Wu, J.R., Chan, K.K., Fu, Y.G., Chan, F.K., Sung, J.J. Gut (2004) [Pubmed]
  36. PKCeta associates with cyclin E/Cdk2 complex in serum-starved MCF-7 and NIH-3T3 cells. Shtutman, M., Hershko, T., Maissel, A., Fima, E., Livneh, E. Exp. Cell Res. (2003) [Pubmed]
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