View source for Biology:Cyclin A2

{{Infobox_gene}}
'''Cyclin-A2''' is a [[Biology:Protein|protein]] that in humans is encoded by the ''CCNA2'' [[Biology:Gene|gene]].<ref name="pmid1675006">{{cite journal | vauthors = Paterlini P, De Mitri MS, Martin C, Münnich A, Bréchot C | title = A TaqI polymorphism in the human cyclin A gene | journal = Nucleic Acids Res. | volume = 19 | issue = 9 | pages = 2516  | date = July 1991 | pmid = 1675006 | pmc = 329485 | doi = 10.1093/nar/19.9.2516 }}</ref> It is one of the two types of [[Biology:Cyclin A|cyclin A]]: [[Biology:Cyclin A1|cyclin A1]] is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells.<ref name="pmid12363035 ">{{cite journal | vauthors = Yam CH, Fung TK, Poon RY | title = Cyclin A in cell cycle control and cancer | journal = Cell. Mol. Life Sci. | volume = 59 | issue = 8 | pages = 1317–1326  | date = Aug 2002 | pmid = 12363035 | doi = 10.1007/s00018-002-8510-y | s2cid = 97398 }}</ref>

== Function ==

Cyclin A2 belongs to the [[Biology:Cyclin|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 [[Biology:Cyclin-dependent kinase 2|CDK2]] during S phase, and [[Biology:Cyclin-dependent kinase 1|CDK1]] during the transition from G2 to M phase.<ref name="pmcid556537">{{cite journal | vauthors = Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G | title = Cyclin A is required at two points in the human cell cycle | journal = EMBO J. | volume = 11 | issue = 3 | pages = 961–971  | date = March 1992 | pmid = 1312467 | pmc = 556537 | doi =  10.1002/j.1460-2075.1992.tb05135.x}}</ref>

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 [[Biology:CDC6|CDC6]] and MCM4 by the cyclin A2-CDK2 complex prevents re-replication of DNA during the cell cycle.<ref name="pmid12363035 "/>

Cyclin A2 is involved in the G2/M transition but it cannot independently form a [[Biology:Maturation promoting factor|maturation promoting factor]] (MPF).<ref name="pmid17344473 ">{{cite journal | vauthors = Fung TK, Ma HT, Poon RY | title = Specialized roles of the two mitotic cyclins in somatic cells: cyclin A as an activator of M phase-promoting factor | journal = Mol. Biol. Cell | volume = 18 | issue = 5 | pages = 1861–1873  | date = Mar 2007 | pmid = 17344473 | pmc = 1855023 | doi = 10.1091/mbc.E06-12-1092 }}</ref> 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.<ref name="pmid20660152 ">{{cite journal | vauthors = Gong D, Ferrell JE | title = The roles of cyclin A2, B1, and B2 in early and late mitotic events | journal = Mol. Biol. Cell | volume = 21 | issue = 18 | pages = 3149–3161  | date = Sep 2010 | pmid = 20660152 | pmc = 2938381 | doi = 10.1091/mbc.E10-05-0393 }}</ref>

== Regulation ==

The levels of cyclin A2 are tightly synchronized with the progression of the cell cycle.<ref name="pmid8202514">{{cite journal | vauthors = Henglein B, Chenivesse X, Wang J, Eick D, Bréchot C | title = Structure and cell cycle-regulated transcription of the human cyclin A gene | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 12 | pages = 5490–5494  | date = Jun 1994 | pmid = 8202514 | pmc = 44021 | doi = 10.1073/pnas.91.12.5490 }}</ref> Transcription initiates in late G1, peaks and plateaus in mid-S, and declines in G2.<ref name="pmid8202514"/><ref name="pmid12363035"/>

Cyclin A2 transcription is mostly regulated by the transcription factor [[Biology:E2F|E2F]] and begins in G1, after the R point.<ref name="pmid8202514"/><ref name="pmid12363035"/> Absence of cyclin A2 before the R point is due to the E2F inhibition by hypophosphorylated [[Biology:Retinoblastoma protein|retinoblastoma protein]] (pRb). After the R point, pRb is phosphorylated and can no longer bind E2F, leading to cyclin A2 transcription.<ref name="pmid12851482">{{cite journal | vauthors = Woo RA, Poon RY | title = Cyclin-dependent kinases and S phase control in mammalian cells | journal = Cell Cycle | volume = 2 | issue = 4 | pages = 316–324 | date = Jul–Aug 2003 | pmid = 12851482 | doi = 10.4161/cc.2.4.468 | doi-access = free }}</ref><ref name="pmid7969176">{{cite journal | vauthors = Xu M, Sheppard KA, Peng CY, Yee AS, Piwnica-Worms H | title = Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation | journal = Mol. Cell. Biol. | volume = 14 | issue = 12 | pages = 8420–8431 | year = 1994 | pmid = 7969176 | pmc = 359381 | doi =  10.1128/MCB.14.12.8420}}</ref> The cyclin A2-CDK2 complex eventually phosphorylates E2F, turning off cyclin A2 transcription.<ref name="pmid8202514"/>  E2F promotes cyclin A2 transcription by de-repressing the promoter.<ref name="pmid8202514"/><ref name="pmid12851482"/>

== Interactions ==

Cyclin A2 has been shown to interact with:
* [[Biology:CDC6|CDC6]],<ref name = pmid9889196>{{cite journal | vauthors = Petersen BO, Lukas J, Sørensen CS, Bartek J, Helin K | title = Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization | journal = EMBO J. | volume = 18 | issue = 2 | pages = 396–410  | date = January 1999 | pmid = 9889196 | pmc = 1171134 | doi = 10.1093/emboj/18.2.396 }}</ref><ref name = pmid9566895>{{cite journal | vauthors = Saha P, Chen J, Thome KC, Lawlis SJ, Hou ZH, Hendricks M, Parvin JD, Dutta A | title = Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase | journal = Mol. Cell. Biol. | volume = 18 | issue = 5 | pages = 2758–2767  | date = May 1998 | pmid = 9566895 | pmc = 110655 | doi =  10.1128/mcb.18.5.2758}}</ref>
* [[Biology:E2F1|E2F1]],<ref name = pmid7969176 />
* FEN1,<ref name = pmid12853968>{{cite journal | vauthors = Henneke G, Koundrioukoff S, Hübscher U | title = Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation | journal = Oncogene | volume = 22 | issue = 28 | pages = 4301–4313  | date = July 2003 | pmid = 12853968 | doi = 10.1038/sj.onc.1206606 | doi-access = free }}</ref>
* [[Biology:ITGB3BP|ITGB3BP]],<ref name = pmid10673397>{{cite journal | vauthors = Ohtoshi A, Maeda T, Higashi H, Ashizawa S, Yamada M, Hatakeyama M | title = beta3-endonexin as a novel inhibitor of cyclin A-associated kinase | journal = Biochem. Biophys. Res. Commun. | volume = 267 | issue = 3 | pages = 947–952  | date = January 2000 | pmid = 10673397 | doi = 10.1006/bbrc.1999.2007 }}</ref>
* [[Biology:Retinoblastoma-like protein 1|RBL1]],<ref name = pmid8230483>{{cite journal | vauthors = Dyson N, Dembski M, Fattaey A, Ngwu C, Ewen M, Helin K | title = Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1 | journal = J. Virol. | volume = 67 | issue = 12 | pages = 7641–7647  | date = December 1993 | pmid = 8230483 | pmc = 238233 | doi =  10.1128/JVI.67.12.7641-7647.1993}}</ref><ref name = pmid12439743>{{cite journal | vauthors = Joaquin M, Bessa M, Saville MK, Watson RJ | title = B-Myb overcomes a p107-mediated cell proliferation block by interacting with an N-terminal domain of p107 | journal = Oncogene | volume = 21 | issue = 52 | pages = 7923–7932  | date = November 2002 | pmid = 12439743 | doi = 10.1038/sj.onc.1206001 | doi-access = free }}</ref>  and
* [[Biology:SKP2|SKP2]].<ref name = pmid15355997>{{cite journal | vauthors = Rosner M, Hengstschläger M | title = Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2 | journal = J. Biol. Chem. | volume = 279 | issue = 47 | pages = 48707–48715  | date = November 2004 | pmid = 15355997 | doi = 10.1074/jbc.M405528200 | doi-access = free }}</ref><ref name = pmid10559858>{{cite journal | vauthors = Marti A, Wirbelauer C, Scheffner M, Krek W | title = Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation | journal = Nat. Cell Biol. | volume = 1 | issue = 1 | pages = 14–19  | date = May 1999 | pmid = 10559858 | doi = 10.1038/8984 | s2cid = 8884226 }}</ref> 
{{Clear}}

== 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.<ref name="Shapiro_2014"/> 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.<ref name="Shapiro_2014"/>

Ccna2 has been found to induce cardiac repair in small-animal models following myocardial infarction.<ref name="Shapiro_2014">{{cite journal | vauthors = Shapiro SD, Ranjan AK, Kawase Y, Cheng RK, Kara RJ, Bhattacharya R, Guzman-Martinez G, Sanz J, Garcia MJ, Chaudhry HW | title = Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes | journal = Sci Transl Med | volume = 6 | issue = 224 | pages = 224ra27 | year = 2014 | pmid = 24553388 | doi = 10.1126/scitranslmed.3007668 | s2cid = 20386712 }}</ref> 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.<ref name="Shapiro_2014"/> 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.<ref name="Shapiro_2014"/> Delivery of Ccna2 into cardiac tissue invokes a regenerative response and markedly enhances cardiac function.<ref name="Shapiro_2014"/><ref name="pmid17382628">{{cite journal | vauthors = Woo YJ, Panlilio CM, Cheng RK, Liao GP, Suarez EE, Atluri P, Chaudhry HW | title = Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2 | journal = J. Thorac. Cardiovasc. Surg. | volume = 133 | issue = 4 | pages = 927–933 | year = 2007 | pmid = 17382628 | doi = 10.1016/j.jtcvs.2006.07.057 }}</ref><ref name="pmid21593865">{{cite journal | vauthors = Laflamme MA, Murry CE | title = Heart regeneration | journal = Nature | volume = 473 | issue = 7347 | pages = 326–335 | year = 2011 | pmid = 21593865 | pmc = 4091722 | doi = 10.1038/nature10147 }}</ref>

== Cancer ==

Increased expression of cyclin A2 has been observed in many types of cancer such as breast, cervical, liver, and lung among others.<ref name="pmid12363035 "/><ref name="pmid11410878">{{cite journal | vauthors = Bukholm IR, Bukholm G, Nesland JM | title = Over-expression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas | journal = Int. J. Cancer | volume = 93 | issue = 2 | pages = 283–287  | date = Jul 2001 | pmid = 11410878 | doi = 10.1002/ijc.1311 | s2cid = 10543682 | doi-access = free }}</ref><ref name="pmid9576293">{{cite journal | vauthors = Kanai M, Shiozawa T, Xin L, Nikaido T, Fujii S | title = Immunohistochemical detection of sex steroid receptors, cyclins, and cyclin-dependent kinases in the normal and neoplastic squamous epithelia of the uterine cervix | journal = Cancer | volume = 82 | issue = 9 | pages = 1709–1719  | date = May 1998 | pmid = 9576293 | doi = 10.1002/(sici)1097-0142(19980501)82:9<1709::aid-cncr18>3.0.co;2-8 }}</ref><ref name="pmid11299822">{{cite journal | vauthors = Ohashi R, Gao C, Miyazaki M, Hamazaki K, Tsuji T, Inoue Y, Uemura T, Hirai R, Shimizu N, Namba M | title = Enhanced expression of cyclin E and cyclin A in human hepatocellular carcinomas | journal = Anticancer Res. | volume = 21 | issue = 1B | pages = 657–662 | date = Jan–Feb 2001 | pmid = 11299822 }}</ref><ref name="pmid9192980">{{cite journal | vauthors = Volm M, Koomägi R, Mattern J, Stammler G | title = Cyclin A is associated with an unfavourable outcome in patients with non-small-cell lung carcinomas | journal = Br. J. Cancer | volume = 75 | issue = 12 | pages = 1774–1778 | year = 1997 | pmid = 9192980 | pmc = 2223613 | doi = 10.1038/bjc.1997.302 }}</ref> 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.<ref name="pmid12363035 "/>

Overexpression of cyclin A2 in mammalian cells can result in the delayed onset of [[Biology:Metaphase|metaphase]] and [[Biology:Anaphase|anaphase]].<ref name="pmid11285279">{{cite journal | vauthors = den Elzen N, Pines J | title = Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase | journal = J. Cell Biol. | volume = 153 | issue = 1 | pages = 121–136  | date = Apr 2001 | pmid = 11285279 | pmc = 2185531 | doi = 10.1083/jcb.153.1.121 }}</ref> It is also possible that cyclin A2-CDK contributes to tumorigenesis by the phosphorylation of [[Biology:Oncogene|oncoproteins]] or tumor suppressors like [[Biology:P53|p53]].<ref name="pmid7596441">{{cite journal | vauthors = Wang Y, Prives C | title = Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases | journal = Nature | volume = 376 | issue = 6535 | pages = 88–91  | date = Jul 1995 | pmid = 7596441 | doi = 10.1038/376088a0 | s2cid = 4240439 }}</ref>

== See also ==
*[[Biology:Cyclin A|Cyclin A]]

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Bailly E, Pines J, Hunter T, Bornens M | title = Cytoplasmic accumulation of cyclin B1 in human cells: association with a detergent-resistant compartment and with the centrosome | journal = J. Cell Sci. | volume = 101 | issue = 3 | pages = 529–545 | year = 1992 | pmid = 1387877 }}
* {{cite journal | vauthors = Faha B, Ewen ME, Tsai LH, Livingston DM, Harlow E | title = Interaction between human cyclin A and adenovirus E1A-associated p107 protein | journal = Science | volume = 255 | issue = 5040 | pages = 87–90 | year = 1992 | pmid = 1532458 | doi = 10.1126/science.1532458 }}
* {{cite journal | vauthors = Bandara LR, Adamczewski JP, Hunt T, La Thangue NB | title = Cyclin A and the retinoblastoma gene product complex with a common transcription factor | journal = Nature | volume = 352 | issue = 6332 | pages = 249–251 | year = 1991 | pmid = 1830372 | doi = 10.1038/352249a0 | s2cid = 1019851 }}
* {{cite journal | vauthors = Blanquet V, Wang JA, Chenivesse X, Henglein B, Garreau F, Bréchot C, Turleau C | title = Assignment of a human cyclin A gene to 4q26-q27 | journal = Genomics | volume = 8 | issue = 3 | pages = 595–597 | year = 1990 | pmid = 1962755 | doi = 10.1016/0888-7543(90)90052-V }}
* {{cite journal | vauthors = Wang J, Chenivesse X, Henglein B, Bréchot C | title = Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma | journal = Nature | volume = 343 | issue = 6258 | pages = 555–557 | year = 1990 | pmid = 1967822 | doi = 10.1038/343555a0 | s2cid = 4269638 }}
* {{cite journal | vauthors = Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP | title = Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex | journal = Nature | volume = 376 | issue = 6538 | pages = 313–320 | year = 1995 | pmid = 7630397 | doi = 10.1038/376313a0 | s2cid = 4361179 }}
* {{cite journal | vauthors = Castro A, Jaumot M, Vergés M, Agell N, Bachs O | title = Microsomal localization of cyclin A and cdk2 in proliferating rat liver cells | journal = Biochem. Biophys. Res. Commun. | volume = 201 | issue = 3 | pages = 1072–1078 | year = 1994 | pmid = 8024548 | doi = 10.1006/bbrc.1994.1814 }}
* {{cite journal | vauthors = Dyson N, Dembski M, Fattaey A, Ngwu C, Ewen M, Helin K | title = Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1 | journal = J. Virol. | volume = 67 | issue = 12 | pages = 7641–7647 | year = 1993 | pmid = 8230483 | pmc = 238233 | doi =  10.1128/JVI.67.12.7641-7647.1993}}
* {{cite journal | vauthors = Li Y, Graham C, Lacy S, Duncan AM, Whyte P | title = The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E | journal = Genes Dev. | volume = 7 | issue = 12A | pages = 2366–2377 | year = 1993 | pmid = 8253383 | doi = 10.1101/gad.7.12a.2366 | doi-access = free }}
* {{cite journal | vauthors = Lees EM, Harlow E | title = Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase | journal = Mol. Cell. Biol. | volume = 13 | issue = 2 | pages = 1194–1201 | year = 1993 | pmid = 8423786 | pmc = 359004 | doi =  10.1128/MCB.13.2.1194}}
* {{cite journal | vauthors = Sebastian B, Kakizuka A, Hunter T | title = Cdc25M2 activation of cyclin-dependent kinases by dephosphorylation of threonine-14 and tyrosine-15 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 90 | issue = 8 | pages = 3521–3524 | year = 1993 | pmid = 8475101 | pmc = 46332 | doi = 10.1073/pnas.90.8.3521 }}
* {{cite journal | vauthors = Carbonaro-Hall D, Williams R, Wu L, Warburton D, Zeichner-David M, MacDougall M, Tolo V, Hall F | title = G1 expression and multistage dynamics of cyclin A in human osteosarcoma cells | journal = Oncogene | volume = 8 | issue = 6 | pages = 1649–1659 | year = 1993 | pmid = 8502485 }}
* {{cite journal | vauthors = Meikrantz W, Schlegel R | title = Suppression of apoptosis by dominant negative mutants of cyclin-dependent protein kinases | journal = J. Biol. Chem. | volume = 271 | issue = 17 | pages = 10205–10209 | year = 1996 | pmid = 8626584 | doi = 10.1074/jbc.271.17.10205 | doi-access = free }}
* {{cite journal | vauthors = Poon RY, Jiang W, Toyoshima H, Hunter T | title = Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage | journal = J. Biol. Chem. | volume = 271 | issue = 22 | pages = 13283–13291 | year = 1996 | pmid = 8662825 | doi = 10.1074/jbc.271.22.13283 | doi-access = free }}
* {{cite journal | vauthors = Russo AA, Jeffrey PD, Patten AK, Massagué J, Pavletich NP | title = Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex | journal = Nature | volume = 382 | issue = 6589 | pages = 325–331 | year = 1996 | pmid = 8684460 | doi = 10.1038/382325a0 | s2cid = 4284942 }}
* {{cite journal | vauthors = Russo AA, Jeffrey PD, Pavletich NP | title = Structural basis of cyclin-dependent kinase activation by phosphorylation | journal = Nat. Struct. Biol. | volume = 3 | issue = 8 | pages = 696–700 | year = 1996 | pmid = 8756328 | doi = 10.1038/nsb0896-696 | s2cid = 383015 }}
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{{Cell cycle proteins}}

[[Category:Cell cycle]]

{{Sourceattribution|Cyclin A2|1}}