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Cyclin E

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cyclin E1
Identifiers
SymbolCCNE1
Alt. symbolsCCNE
NCBI gene898
HGNC1589
OMIM123837
RefSeqNM_001238
UniProtP24864
Other data
LocusChr. 19 q12
Search for
StructuresSwiss-model
DomainsInterPro
cyclin E2
Identifiers
SymbolCCNE2
NCBI gene9134
HGNC1590
OMIM603775
RefSeqNM_057749
UniProtO96020
Other data
LocusChr. 8 q22.1
Search for
StructuresSwiss-model
DomainsInterPro

Cyclin E is a member of the cyclin family.

Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines cell division. The Cyclin E/CDK2 complex phosphorylates p27Kip1 (an inhibitor of Cyclin D), tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase.

Expression of cyclins through the cell cycle.
Expression of cyclins through the cell cycle.

Functions of Cyclin E

Like all cyclin family members, cyclin E forms a complex with cyclin-dependent kinase (CDK2). Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins.

Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase.[1] Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression.[2] CBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression.[3] Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression.[4]

Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle. This function is performed by phosphorylating nucleophosmin (NPM). Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication.[5] CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation.[6] Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1.[7]

Cyclin E and Cancer

Over-expression of cyclin E correlates with tumorigenesis. It is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer.[8] Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence.[9][10]

Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression.[11] Proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in several cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination.[12] Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation.

Dysregulation of cyclin E occurs in 18-22% of the breast cancers. Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor.[13] Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer.[14] These isoforms are resistant to CKIs, bind with CDK2 more efficiently and can stimulate the cell cycle progression more efficiently. They are proved to be a remarkable marker of the prognosis of early-stage-node negative breast cancer.[15] Importantly, a recent research pointed out cyclin E overexpression is a mechanism of Trastuzumab resistance in HER2+ breast cancer patients. Thus, co-treatment of trastuzumab with CDK2 inhibitors may be a valid strategy.[16]

Cyclin E overexpression is implicated in carcinomas at various sites along the gastrointestinal tract. Among these carcinomas, cyclin E appears to be more important in stomach and colon cancer. Cyclin E overexpression was found in 50-60% of gastric adenomas and adenocarcinomas.[17] In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification.[18]

Cyclin E is also a useful prognostic marker for lung cancer. There is significant association between cyclin E over-expression and the prognosis of lung cancer. It is believed increased expression of cyclin E correlated with poorer prognosis.[19]

References

  1. ^ Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992, 70: 993-1006
  2. ^ Cooley A, Zelivianski S, Jeruss JS. Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines. Cell Cycle. 2010, 9: 4900-4907
  3. ^ Morris L, Allen KE, La Thangue NB. Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators. Nat Cell Biol. 2000, 2: 232-239
  4. ^ Ma T, Van Tine BA, Wei Y, et al. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. Genes Dev. 2000, 14: 2298-2313
  5. ^ Okuda M, Horn HF, Tarapore P, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000, 103: 127-140
  6. ^ Chen Z, Indjeian VB, McManus M, et al. CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev Cell. 2002, 3: 339-350
  7. ^ Huang H, Regan KM, Lou Z, et al. Cdk2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science. 2006, 314: 294-297
  8. ^ Donnellan R and Chetty R. Cyclin E in human cancers. FASEB J. 1999, 13: 773-780
  9. ^ Minella AC, Loeb KR, Knecht A, et al. Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev. 2008, 22: 1677-1689
  10. ^ Kossatz U, Breuhahn K, Wolf B, et al. The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. J Clin Invest. 2010, 120: 3820-3833
  11. ^ Geisen C, Moroy T. The oncogenic activity of cyclin E is not confirmed to Cdk2 activation alone but relies on several other, distinct functions of the protein. J Biol Chem. 2002, 277: 39909-39918
  12. ^ Buckley MF, Sweeney KJ, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993, 8: 2127-2133
  13. ^ Keyomarsi K, O’Leary N, Molnar G, et al. Cyclin E, a potential prognostic marker for breast cancer. Cancer Research. 1994. 54: 380-385.
  14. ^ Wingate H, Puskas A, Duong M, et al. Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression. Cell Cycle. 2009, 8: 1062-1068
  15. ^ Keyomarsi K, Tucker SL, Buchholz TA, et al. Cyclin E and survival in patients with breast cancer. NEJM 2002, 347: 1566-1575
  16. ^ Scaltriti M, Eichhorn PJ, Cortes J, et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. PNAS. 2011, 108: 3761-3766
  17. ^ Yasui W, Akama Y, Kuniyasu H, Yokozaki H, et al. Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status. Exp Ther Oncol. 1996, 1: 88-94
  18. ^ Kitahara K, Yasui W, Kuniyasu H, et al. Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas. Int. J. Cancer. 1995, 62: 25-28
  19. ^ Huang L, Wang D, Chen Y, et al. Meta-analysis for cyclin E in lung cancer survival. Clinica Chimica Acta. 2012, 413: 663-668
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