Cyclin E

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.
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.

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] 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]

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References
  1. Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA (September 1992). "Regulation of retinoblastoma protein functions by ectopic expression of human cyclins". Cell. 70 (6): 993–1006. doi:10.1016/0092-8674(92)90249-c. PMID 1388095.
  2. 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.
  3. Morris L, Allen KE, La Thangue NB (April 2000). "Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators". Nature Cell Biology. 2 (4): 232–9. doi:10.1038/35008660. PMID 10783242.
  4. 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.
  5. 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.
  6. 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.
  7. 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. doi:10.1126/science.1130512. PMID 17038621.
  8. 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.
  9. 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. doi:10.1371/journal.pone.0030098. PMC 3264559. PMID 22291905.
  10. 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. doi:10.1371/journal.pone.0164546. PMC 5087864. PMID 27798635.
  11. 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.
  12. 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.
  13. 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.
  14. Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CK, Musgrove EA, Sutherland RL (August 1993). "Expression and amplification of cyclin genes in human breast cancer". Oncogene. 8 (8): 2127–33. PMID 8336939.
  15. Keyomarsi K, O'Leary N, Molnar G, Lees E, Fingert HJ, Pardee AB (January 1994). "Cyclin E, a potential prognostic marker for breast cancer". Cancer Research. 54 (2): 380–5. PMID 7903908.
  16. 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.
  17. 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.
  18. 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. doi:10.1073/pnas.1014835108. PMC 3048107. PMID 21321214.
  19. Yasui W, Akama Y, Kuniyasu H, Yokozaki H, Semba S, Shimamoto F, Tahara E (March 1996). "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. PMID 9414392.
  20. Kitahara K, Yasui W, Kuniyasu H, Yokozaki H, Akama Y, Yunotani S, Hisatsugu T, Tahara E (July 1995). "Concurrent amplification of cyclin E and CDK2 genes in colorectal carcinomas". International Journal of Cancer. 62 (1): 25–8. doi:10.1002/ijc.2910620107. PMID 7601562.
  21. 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.
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