Biology:Cyclin A2

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Generic protein structure example

Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene.[1] It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells.[2]

Function

Cyclin A2 belongs to the cyclin family, whose members regulate cell cycle progression by interacting with CDK kinases. Cyclin A2 is unique in that it can activate two different CDK kinases; it binds CDK2 during S phase, and CDK1 during the transition from G2 to M phase.[3]

Cyclin A2 is synthesized at the onset of S phase and localizes to the nucleus, where the cyclin A2-CDK2 complex is implicated in the initiation and progression of DNA synthesis. Phosphorylation of CDC6 and MCM4 by the cyclin A2-CDK2 complex prevents re-replication of DNA during the cell cycle.[2]

Cyclin A2 is involved in the G2/M transition but it cannot independently form a maturation promoting factor (MPF).[4] Recent studies have shown that the cyclin A2-CDK1 complex triggers cyclin B1-CDK1 activation which results in chromatin condensation and the breakdown of the nuclear envelope.[5]

Regulation

The levels of cyclin A2 are tightly synchronized with the progression of the cell cycle.[6] Transcription initiates in late G1, peaks and plateaus in mid-S, and declines in G2.[6][2]

Cyclin A2 transcription is mostly regulated by the transcription factor E2F and begins in G1, after the R point.[6][2] Absence of cyclin A2 before the R point is due to the E2F inhibition by hypophosphorylated retinoblastoma protein (pRb). After the R point, pRb is phosphorylated and can no longer bind E2F, leading to cyclin A2 transcription.[7][8] The cyclin A2-CDK2 complex eventually phosphorylates E2F, turning off cyclin A2 transcription.[6] E2F promotes cyclin A2 transcription by de-repressing the promoter.[6][7]

Interactions

Cyclin A2 has been shown to interact with:

Clinical significance

Cyclin A2 (Ccna2) is a key protein involved in the direction of mammalian cardiac myocytes to grow and divide, and has been shown to induce cardiac repair following myocardial infarction.[17] Normally, Ccna2 is silenced postnatally in mammalian cardiac myocytes. Because of this gene silencing, adult heart muscle cells cannot divide readily to repair and regenerate after a heart attack.[17]

Ccna2 has been found to induce cardiac repair in small-animal models following myocardial infarction.[17] Preclinical trials involving injections of adenovirus which contained the Ccna2 gene into infarcted porcine (pig) hearts has shown to be protective of MI in pig hearts.[17] Ccna2 mediated cardiac repair showed both a decrease in fibrosis in the peri-infarct tissue and a greater number of cardiomyocytes at the sites of injection.[17] Delivery of Ccna2 into cardiac tissue invokes a regenerative response and markedly enhances cardiac function.[17][18][19]

Cancer

Increased expression of cyclin A2 has been observed in many types of cancer such as breast, cervical, liver, and lung among others.[2][20][21][22][23] While it is not clear whether increased expression of cyclin A2 is a cause or result of tumorigenesis, it is indicative of prognostic values such as predictions of survival or relapse.[2]

Overexpression of cyclin A2 in mammalian cells can result in the delayed onset of metaphase and anaphase.[24] It is also possible that cyclin A2-CDK contributes to tumorigenesis by the phosphorylation of oncoproteins or tumor suppressors like p53.[25]

See also

References

  1. ↑ "A TaqI polymorphism in the human cyclin A gene". Nucleic Acids Res. 19 (9): 2516. July 1991. doi:10.1093/nar/19.9.2516. PMID 1675006. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Cyclin A in cell cycle control and cancer". Cell. Mol. Life Sci. 59 (8): 1317–1326. Aug 2002. doi:10.1007/s00018-002-8510-y. PMID 12363035. 
  3. ↑ "Cyclin A is required at two points in the human cell cycle". EMBO J. 11 (3): 961–971. March 1992. doi:10.1002/j.1460-2075.1992.tb05135.x. PMID 1312467. 
  4. ↑ "Specialized roles of the two mitotic cyclins in somatic cells: cyclin A as an activator of M phase-promoting factor". Mol. Biol. Cell 18 (5): 1861–1873. Mar 2007. doi:10.1091/mbc.E06-12-1092. PMID 17344473. 
  5. ↑ "The roles of cyclin A2, B1, and B2 in early and late mitotic events". Mol. Biol. Cell 21 (18): 3149–3161. Sep 2010. doi:10.1091/mbc.E10-05-0393. PMID 20660152. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Structure and cell cycle-regulated transcription of the human cyclin A gene". Proc. Natl. Acad. Sci. U.S.A. 91 (12): 5490–5494. Jun 1994. doi:10.1073/pnas.91.12.5490. PMID 8202514. 
  7. ↑ 7.0 7.1 "Cyclin-dependent kinases and S phase control in mammalian cells". Cell Cycle 2 (4): 316–324. Jul–Aug 2003. doi:10.4161/cc.2.4.468. PMID 12851482. 
  8. ↑ 8.0 8.1 "Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation". Mol. Cell. Biol. 14 (12): 8420–8431. 1994. doi:10.1128/MCB.14.12.8420. PMID 7969176. 
  9. ↑ "Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization". EMBO J. 18 (2): 396–410. January 1999. doi:10.1093/emboj/18.2.396. PMID 9889196. 
  10. ↑ "Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase". Mol. Cell. Biol. 18 (5): 2758–2767. May 1998. doi:10.1128/mcb.18.5.2758. PMID 9566895. 
  11. ↑ "Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation". Oncogene 22 (28): 4301–4313. July 2003. doi:10.1038/sj.onc.1206606. PMID 12853968. 
  12. ↑ "beta3-endonexin as a novel inhibitor of cyclin A-associated kinase". Biochem. Biophys. Res. Commun. 267 (3): 947–952. January 2000. doi:10.1006/bbrc.1999.2007. PMID 10673397. 
  13. ↑ "Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1". J. Virol. 67 (12): 7641–7647. December 1993. doi:10.1128/JVI.67.12.7641-7647.1993. PMID 8230483. 
  14. ↑ "B-Myb overcomes a p107-mediated cell proliferation block by interacting with an N-terminal domain of p107". Oncogene 21 (52): 7923–7932. November 2002. doi:10.1038/sj.onc.1206001. PMID 12439743. 
  15. ↑ "Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2". J. Biol. Chem. 279 (47): 48707–48715. November 2004. doi:10.1074/jbc.M405528200. PMID 15355997. 
  16. ↑ "Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation". Nat. Cell Biol. 1 (1): 14–19. May 1999. doi:10.1038/8984. PMID 10559858. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 "Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes". Sci Transl Med 6 (224): 224ra27. 2014. doi:10.1126/scitranslmed.3007668. PMID 24553388. 
  18. ↑ "Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2". J. Thorac. Cardiovasc. Surg. 133 (4): 927–933. 2007. doi:10.1016/j.jtcvs.2006.07.057. PMID 17382628. 
  19. ↑ "Heart regeneration". Nature 473 (7347): 326–335. 2011. doi:10.1038/nature10147. PMID 21593865. 
  20. ↑ "Over-expression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas". Int. J. Cancer 93 (2): 283–287. Jul 2001. doi:10.1002/ijc.1311. PMID 11410878. 
  21. ↑ "Immunohistochemical detection of sex steroid receptors, cyclins, and cyclin-dependent kinases in the normal and neoplastic squamous epithelia of the uterine cervix". Cancer 82 (9): 1709–1719. May 1998. doi:10.1002/(sici)1097-0142(19980501)82:9<1709::aid-cncr18>3.0.co;2-8. PMID 9576293. 
  22. ↑ "Enhanced expression of cyclin E and cyclin A in human hepatocellular carcinomas". Anticancer Res. 21 (1B): 657–662. Jan–Feb 2001. PMID 11299822. 
  23. ↑ "Cyclin A is associated with an unfavourable outcome in patients with non-small-cell lung carcinomas". Br. J. Cancer 75 (12): 1774–1778. 1997. doi:10.1038/bjc.1997.302. PMID 9192980. 
  24. ↑ "Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase". J. Cell Biol. 153 (1): 121–136. Apr 2001. doi:10.1083/jcb.153.1.121. PMID 11285279. 
  25. ↑ "Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases". Nature 376 (6535): 88–91. Jul 1995. doi:10.1038/376088a0. PMID 7596441. 

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