Cyclin_E
Cyclin E
Member of the cyclin family
Cyclin E is a member of the cyclin family.
cyclin E1 | |||||||
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Identifiers | |||||||
Symbol | CCNE1 | ||||||
Alt. symbols | CCNE | ||||||
NCBI gene | 898 | ||||||
HGNC | 1589 | ||||||
OMIM | 123837 | ||||||
RefSeq | NM_001238 | ||||||
UniProt | P24864 | ||||||
Other data | |||||||
Locus | Chr. 19 q12 | ||||||
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cyclin E2 | |||||||
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Identifiers | |||||||
Symbol | CCNE2 | ||||||
NCBI gene | 9134 | ||||||
HGNC | 1590 | ||||||
OMIM | 603775 | ||||||
RefSeq | NM_057749 | ||||||
UniProt | O96020 | ||||||
Other data | |||||||
Locus | Chr. 8 q22.1 | ||||||
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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.
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]
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]
- Cooley A, Zelivianski S, Jeruss JS (December 2010). "Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines". Cell Cycle. 9 (24): 4900–7. doi:10.4161/cc.9.24.14158. PMC 3047813. PMID 21150326.
- Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW (September 2000). "Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription". Genes & Development. 14 (18): 2298–313. doi:10.1101/gad.829500. PMC 316935. PMID 10995387.
- Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K (September 2000). "Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication". Cell. 103 (1): 127–40. doi:10.1016/S0092-8674(00)00093-3. PMID 11051553. S2CID 18705905.
- Chen Z, Indjeian VB, McManus M, Wang L, Dynlacht BD (September 2002). "CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells". Developmental Cell. 3 (3): 339–50. doi:10.1016/s1534-5807(02)00258-7. PMID 12361598.
- Huang H, Regan KM, Lou Z, Chen J, Tindall DJ (October 2006). "CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage". Science. 314 (5797): 294–7. Bibcode:2006Sci...314..294H. doi:10.1126/science.1130512. PMID 17038621. S2CID 967645.
- Donnellan R, Chetty R (May 1999). "Cyclin E in human cancers". FASEB Journal. 13 (8): 773–80. doi:10.1096/fasebj.13.8.773. PMID 10224221. S2CID 11535791.
- Lee CH, Alpert BO, Sankaranarayanan P, Alter O (January 2012). "GSVD comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival". PLOS ONE. 7 (1): e30098. Bibcode:2012PLoSO...730098L. doi:10.1371/journal.pone.0030098. PMC 3264559. PMID 22291905.
- Aiello KA, Alter O (October 2016). "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. Bibcode:2016PLoSO..1164546A. doi:10.1371/journal.pone.0164546. PMC 5087864. PMID 27798635.
- Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney BJ, Bernstein ID, Roberts JM, Clurman BE (June 2008). "Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo". Genes & Development. 22 (12): 1677–89. doi:10.1101/gad.1650208. PMC 2428064. PMID 18559482.
- Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP (November 2010). "The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells" (PDF). The Journal of Clinical Investigation. 120 (11): 3820–33. doi:10.1172/JCI41959. PMC 2964969. PMID 20978349.
- Geisen C, Moroy T (October 2002). "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. doi:10.1074/jbc.M205919200. PMID 12149264.
- Wingate H, Puskas A, Duong M, Bui T, Richardson D, Liu Y, Tucker SL, Van Pelt C, Meijer L, Hunt K, Keyomarsi K (April 2009). "Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression". Cell Cycle. 8 (7): 1062–8. doi:10.4161/cc.8.7.8119. PMC 2692060. PMID 19305161.
- Sutherland RL, Musgrove EA (November 2002). "Cyclin E and prognosis in patients with breast cancer". The New England Journal of Medicine. 347 (20): 1546–7. doi:10.1056/NEJMNEJMp020124. PMID 12432040.
- Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, et al. (March 2011). "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. Bibcode:2011PNAS..108.3761S. doi:10.1073/pnas.1014835108. PMC 3048107. PMID 21321214.
- Huang LN, Wang DS, Chen YQ, Li W, Hu FD, Gong BL, Zhao CL, Jia W (April 2012). "Meta-analysis for cyclin E in lung cancer survival". Clinica Chimica Acta; International Journal of Clinical Chemistry. 413 (7–8): 663–8. doi:10.1016/j.cca.2011.12.020. PMID 22244930.
- Cyclin+E at the U.S. National Library of Medicine Medical Subject Headings (MeSH)