Biology:Cyclin E

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Short description: Member of the cyclin family
cyclin E1
Identifiers
SymbolCCNE1
Alt. symbolsCCNE
NCBI gene898
HGNC1589
OMIM123837
RefSeqNM_001238
UniProtP24864
Other data
LocusChr. 19 q12
cyclin E2
Identifiers
SymbolCCNE2
NCBI gene9134
HGNC1590
OMIM603775
RefSeqNM_057749
UniProtO96020
Other data
LocusChr. 8 q22.1

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 initiation of DNA duplication. 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.

Functions of Cyclin E

Like all cyclin family members, cyclin E forms complexes with cyclin-dependent kinases. In particular, Cyclin E binds with 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] DNA copy-number amplification of cyclin E1 is involved in brain cancer.[9][10] Besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence.[11][12]

Several mechanisms lead to the deregulated expression of cyclin E. In most cases, gene amplification causes the overexpression.[13] 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.[14] 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.[15] Low molecular weight cyclin E isoforms have been shown to be of great pathogenetic and prognostic importance for breast cancer.[16] 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.[17] 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.[18]

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.[19] In ~10% of colorectal carcinomas, cyclin E gene amplification is found, sometimes together with CDK2 gene amplification.[20]

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.[21]

References

  1. ↑ "Regulation of retinoblastoma protein functions by ectopic expression of human cyclins". Cell 70 (6): 993–1006. September 1992. doi:10.1016/0092-8674(92)90249-c. PMID 1388095. 
  2. ↑ "Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines". Cell Cycle 9 (24): 4900–7. December 2010. doi:10.4161/cc.9.24.14158. PMID 21150326. 
  3. ↑ "Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators". Nature Cell Biology 2 (4): 232–9. April 2000. doi:10.1038/35008660. PMID 10783242. 
  4. ↑ "Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription". Genes & Development 14 (18): 2298–313. September 2000. doi:10.1101/gad.829500. PMID 10995387. 
  5. ↑ "Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication". Cell 103 (1): 127–40. September 2000. doi:10.1016/S0092-8674(00)00093-3. PMID 11051553. 
  6. ↑ "CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells". Developmental Cell 3 (3): 339–50. September 2002. doi:10.1016/s1534-5807(02)00258-7. PMID 12361598. 
  7. ↑ "CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage". Science 314 (5797): 294–7. October 2006. doi:10.1126/science.1130512. PMID 17038621. Bibcode: 2006Sci...314..294H. 
  8. ↑ "Cyclin E in human cancers". FASEB Journal 13 (8): 773–80. May 1999. doi:10.1096/fasebj.13.8.773. PMID 10224221. 
  9. ↑ "GSVD comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival". PLOS ONE 7 (1): e30098. January 2012. doi:10.1371/journal.pone.0030098. PMID 22291905. Bibcode: 2012PLoSO...730098L. 
  10. ↑ "Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition". PLOS ONE 11 (10): e0164546. October 2016. doi:10.1371/journal.pone.0164546. PMID 27798635. Bibcode: 2016PLoSO..1164546A. 
  11. ↑ "Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo". Genes & Development 22 (12): 1677–89. June 2008. doi:10.1101/gad.1650208. PMID 18559482. 
  12. ↑ "The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells". The Journal of Clinical Investigation 120 (11): 3820–33. November 2010. doi:10.1172/JCI41959. PMID 20978349. PMC 2964969. https://infoscience.epfl.ch/record/182087/files/JCI41959.pdf. 
  13. ↑ "The oncogenic activity of cyclin E is not confined to Cdk2 activation alone but relies on several other, distinct functions of the protein". The Journal of Biological Chemistry 277 (42): 39909–18. October 2002. doi:10.1074/jbc.M205919200. PMID 12149264. 
  14. ↑ "Expression and amplification of cyclin genes in human breast cancer". Oncogene 8 (8): 2127–33. August 1993. PMID 8336939. 
  15. ↑ "Cyclin E, a potential prognostic marker for breast cancer". Cancer Research 54 (2): 380–5. January 1994. PMID 7903908. 
  16. ↑ "Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression". Cell Cycle 8 (7): 1062–8. April 2009. doi:10.4161/cc.8.7.8119. PMID 19305161. 
  17. ↑ "Cyclin E and prognosis in patients with breast cancer". The New England Journal of Medicine 347 (20): 1546–7. November 2002. doi:10.1056/NEJMNEJMp020124. PMID 12432040. 
  18. ↑ "Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients". Proceedings of the National Academy of Sciences of the United States of America 108 (9): 3761–6. March 2011. doi:10.1073/pnas.1014835108. PMID 21321214. Bibcode: 2011PNAS..108.3761S. 
  19. ↑ "Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status". Journal of Experimental Therapeutics & Oncology 1 (2): 88–94. March 1996. PMID 9414392. 
  20. ↑ "Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas". International Journal of Cancer 62 (1): 25–8. July 1995. doi:10.1002/ijc.2910620107. PMID 7601562. 
  21. ↑ "Meta-analysis for cyclin E in lung cancer survival". Clinica Chimica Acta; International Journal of Clinical Chemistry 413 (7–8): 663–8. April 2012. doi:10.1016/j.cca.2011.12.020. PMID 22244930. 

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