Cyclin A

{{Short description|Protein family}} {{protein |Name=cyclin A1 |caption= |image= |width= |HGNCid=1577 |Symbol=CCNA1 |AltSymbols= |EntrezGene=8900 |OMIM=604036 |RefSeq=NM_003914 |UniProt=P78396 |PDB= |ECnumber= |Chromosome=13 |Arm=q |Band=12.3 |LocusSupplementaryData=-q13 }} {{protein |Name=cyclin A2 |caption= |image= |width= |HGNCid=1578 |Symbol=CCNA2 |AltSymbols=CCNA, CCN1 |EntrezGene=890 |OMIM=123835 |RefSeq=NM_001237 |UniProt=P20248 |PDB= |ECnumber= |Chromosome=4 |Arm=q |Band=27 |LocusSupplementaryData= }} '''Cyclin A''' is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle.<ref name=1-Bendris>{{cite journal | vauthors = Bendris N, Lemmers B, Blanchard JM, Arsic N | title = Cyclin A2 mutagenesis analysis: a new insight into CDK activation and cellular localization requirements | journal = PLOS ONE | volume = 6 | issue = 7 | article-number = e22879 | year = 2011 | pmid = 21829545 | pmc = 3145769 | doi = 10.1371/journal.pone.0022879 | bibcode = 2011PLoSO...622879B | doi-access = free }}</ref> The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle<ref name=textbook>{{cite book | author = Weinberg RE | title = The biology of cancer | publisher = Garland Science | location = New York | year = 2007 | isbn = 978-0-8153-4076-8 }}</ref> Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.<ref name=1-Bendris /><ref name=6Henglein>{{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 = 5490–4 |date=June 1994 | pmid = 8202514 | pmc = 44021 | doi = 10.1073/pnas.91.12.5490| bibcode = 1994PNAS...91.5490H | doi-access = free }}</ref>

==Types== Cyclin A was first identified in 1983 in sea urchin embryos.<ref name="pmid6134587">{{cite journal | vauthors = Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T | title = Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division | journal = Cell | volume = 33 | issue = 2 | pages = 389–96 |date=June 1983 | pmid = 6134587 | doi = 10.1016/0092-8674(83)90420-8| doi-access = free }}</ref> Since its initial discovery, homologues of cyclin A have been identified in numerous eukaryotes including ''Drosophila'',<ref name=8-Huet>{{cite journal | vauthors = Huet X, Rech J, Plet A, Vié A, Blanchard JM | title = Cyclin A expression is under negative transcriptional control during the cell cycle | journal = Mol. Cell. Biol. | volume = 16 | issue = 7 | pages = 3789–98 |date=July 1996 | pmid = 8668196 | pmc = 231375 | doi = 10.1128/mcb.16.7.3789}}</ref> ''Xenopus'', mice, and in humans but has not been found in lower eukaryotes like yeast.<ref name=11-Pagano>{{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 = 961–71 |date=March 1992 | pmid = 1312467 | pmc = 556537 | doi = 10.1002/j.1460-2075.1992.tb05135.x}}</ref><ref name=15yam>{{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 = 1317–26 |date=August 2002 | pmid = 12363035 | doi = 10.1007/s00018-002-8510-y| s2cid = 97398 | pmc = 11337442 }}</ref> The protein exists in both an embryonic form and somatic form. A single cyclin A gene has been identified in Drosophila while Xenopus, mice and humans contain two distinct types of cyclin A: A1, the embryonic-specific form, and A2, the somatic form. Cyclin A1 is prevalently expressed during meiosis and early on in embryogenesis. Cyclin A2 is expressed in dividing somatic cells.<ref name=15yam />

==Role in cell cycle progression== [[File:Cyclin Expression.svg|left|422px|Expression of human cyclins through the cell cycle]] Cyclin A, along with the other members of the cyclin family, regulates '''cell cycle progression''' through physically interacting with cyclin-dependent kinases (CDKs),<ref name="3 deboer">{{cite journal | vauthors = De Boer L, Oakes V, Beamish H, Giles N, Stevens F, Somodevilla-Torres M, Desouza C, Gabrielli B | title = Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events | journal = Oncogene | volume = 27 | issue = 31 | pages = 4261–8 |date=July 2008 | pmid = 18372919 | doi = 10.1038/onc.2008.74 | doi-access = free }}</ref><ref name=16soucek>{{cite journal | vauthors = Soucek T, Pusch O, Hengstschläger-Ottnad E, Adams PD, Hengstschläger M | title = Deregulated expression of E2F-1 induces cyclin A- and E-associated kinase activities independently from cell cycle position | journal = Oncogene | volume = 14 | issue = 19 | pages = 2251–7 |date=May 1997 | pmid = 9178900 | doi = 10.1038/sj.onc.1201061 | doi-access = free }}</ref> which thereby activates the enzymatic activity of its CDK partner.<ref name=1-Bendris /><ref name=textbook /><ref name="3 deboer" />

===CDK partner association===

The interaction between the cyclin box, a region conserved across cyclins, and a region of the CDK, called the PSTAIRE, confers the foundation of the cyclin-CDK complex.<ref name="9 Jeffrey">{{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 = 313–20 |date=July 1995 | pmid = 7630397 | doi = 10.1038/376313a0 | bibcode = 1995Natur.376..313J | s2cid = 4361179 }}</ref> Cyclin A is the only cyclin that regulates multiple steps of the cell cycle.<ref name=15yam /> Cyclin A can regulate multiple cell cycle steps because it associates with, and thereby activates, two distinct CDKs – CDK2 and CDK1.<ref name=1-Bendris /> Depending on which CDK partner cyclin A binds, the cell will continue through the S phase or it will transition from G₂ to the M phase.<ref name=1-Bendris /><ref name=6Henglein /><ref name="9 Jeffrey" /> Association of cyclin A with CDK2 is required for passage into S phase while association with CDK1 is required for entry into M phase.<ref name="9 Jeffrey" />

===S phase===

Cyclin A resides in the nucleus during '''S phase''' where it is involved in the initiation and completion of DNA replication.<ref name=1-Bendris /><ref name=11-Pagano /><ref name=16soucek /> As the cell passes from G₁ into S phase, cyclin A associates with CDK2, replacing cyclin E. Cyclin E is responsible for initiating the assembly of the pre-replication complex. This complex makes chromatin capable of replication. When the amount of cyclin A/CDK2 complex reaches a threshold level, it terminates the assembly of the pre-replication complex made by cyclin E/CDK2. As the amount of Cyclin A/CDK2 complex increases, the complex initiates DNA replication.<ref name="2 coverley">{{cite journal | vauthors = Coverley D, Laman H, Laskey RA | title = Distinct roles for cyclins E and A during DNA replication complex assembly and activation | journal = Nat. Cell Biol. | volume = 4 | issue = 7 | pages = 523–8 |date=July 2002 | pmid = 12080347 | doi = 10.1038/ncb813 | s2cid = 4667087 }}</ref>

Cyclin A has a second function in S phase. In addition to initiating DNA synthesis, Cyclin A ensures that DNA is replicated once per cell cycle by preventing the assembly of additional replication complexes.<ref name=15yam /><ref name="2 coverley" /><ref name="14 woo">{{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 = 316–24 | year = 2003 | pmid = 12851482 | doi = 10.4161/cc.2.4.468| doi-access = free }}</ref> This is thought to occur through the phosphorylation of particular DNA replication machinery components, such as CDC6, by the cyclin A/CDK2 complex.<ref name=1-Bendris /><ref name=15yam /> Since the action of cyclin A/CDK2 inhibits that of cyclin E/CDK2, the sequential activation of cyclin E followed by the activation of cyclin A is important and tightly regulated in S phase.<ref name=15yam /><ref name="2 coverley" />

===G₂ / M phase===

In late S phase, cyclin A can also associate with CDK1.<ref name=1-Bendris /><ref name=textbook /><ref name=15yam /> Cyclin A remains associated with CDK1 from late S into late '''G₂ phase''' when it is replaced by cyclin B. Cyclin A/CDK1 is thought to be involved in the activation and stabilization of cyclin B/CDK1 complex.<ref name=15yam /><ref name="3 deboer" /> Once cyclin B is activated, cyclin A is no longer needed and is subsequently degraded through the ubiquitin pathway.<ref name=6Henglein /><ref name=15yam /> Degradation of cyclin A/CDK1 induces mitotic exit.<ref name=15yam />

Cyclin A/CDK2 complex was thought to be restricted to the nucleus and thus exclusively involved in S phase progression. New research has since debunked this assumption, shedding light on cyclin A/CDK2 migration to the centrosomes in late G₂.<ref name=1-Bendris /><ref name="3 deboer" /> Cyclin A binds to the mitotic spindle poles in the centrosome however, the mechanism by which the complex is shuttled to the centrosome is not well understood. It is suspected that the presence of cyclin A/CDK2 at the centrosomes may confer a means of regulating the movement of cyclin B/CDK1 to the centrosome and thus the timing of mitotic events.<ref name=1-Bendris /><ref name=11-Pagano /><ref name="3 deboer" />

A study in 2008<ref name="3 deboer" /> provided further evidence of cyclin A/CDK2 complex's role in mitosis. Cells were modified so their CDK2 was inhibited and their cyclin A2 gene was knocked out. These mutants entered mitosis late due to a delayed activation of the cyclin B/CDK1 complex. Coupling of microtubule nucleation in the centrosome with mitotic events in the nucleus was lost in the cyclin A knockout/CDK2 inhibited mutant cells.

Cyclin A has been shown to play a crucial role in the G₂/M transition in ''Drosophila'' and ''Xenopus'' embryos.<ref name=6Henglein /><ref name=11-Pagano />

==Regulation== Transcription of cyclin A is tightly regulated and synchronized with cell cycle progression.<ref name=textbook /><ref name=6Henglein /> Initiation of transcription of cyclin A is coordinated with passage of the R point,<ref name=textbook /> a critical transition point that is required for progression from G₁ into S phase. Transcription peaks and plateaus mid-S phase and abruptly declines in late G₂.<ref name=15yam /><ref name="14 woo" />

===E2F and pRb=== Transcription of cyclin A is predominantly regulated by the transcription factor '''E2F''' in a negative feedback loop. E2F is responsible for initiating the transcription of many critical S phase genes.<ref name=1-Bendris /><ref name=6Henglein /><ref name=11-Pagano /> Cyclin A transcription is off during most of G₁ and the begins shortly after the R point.<ref name=6Henglein /><ref name=15yam />

The retinoblastoma protein (pRb) is involved in the regulation of cyclin A through its interaction with E2F. It exists in two states: hypophosphorylated pRb and hyperphosphorylated pRb.<ref name=textbook /> Hypophosphorylated pRb binds E2F, which prevents transcription of cyclin A. The absence of cyclin A prior to the R point is due to the inhibition of E2F by hypophosphorylated pRb. After the cell passes through the R point, cyclin D/E- complexes phosphorylate pRb. Hyperphosphorylated pRb can no longer bind E2F, E2F is released and cyclin A genes, and other crucial genes for S phase, are transcribed.<ref name=textbook /><ref name=16soucek /><ref name="14 woo" />

E2F initiates transcription of cyclin A by de-repressing the promoter.<ref name=15yam /><ref name="14 woo" /> The promoter is bound by a repressor molecule called the cell-cycle-responsive element (CCRE). E2F binds to an E2F binding site on the CCRE, releasing the repressor from the promoter and allowing the transcription of cyclin A.<ref name=8-Huet /><ref name=15yam /> Cyclin A/CDK2 will eventually phosphorylate E2F when cyclin A reaches a certain level, completing the negative feedback loop. Phosphorylation of E2F turns the transcription factor off, providing another level of controlling the transcription of cyclin A.<ref name=15yam />

===p53 and p21===

Transcription of cyclin A is indirectly regulated by the tumor suppressor protein '''p53'''. P53 is activated by DNA damage and turns on several downstream pathways, including cell cycle arrest. Cell cycle arrest is carried out by the p53-pRb pathway.<ref name=17-levine>{{cite journal | author = Levine AJ | title = p53, the cellular gatekeeper for growth and division | journal = Cell | volume = 88 | issue = 3 | pages = 323–31 |date=February 1997 | pmid = 9039259 | doi = 10.1016/S0092-8674(00)81871-1| s2cid = 17192968 | doi-access = free }}</ref> Activated p53 turns on genes for p21. P21 is a CDK inhibitor that binds to several cyclin/CDK complexes, including cyclin A-CDK2/1 and cyclin D/CDK4, and blocks the kinase activity of CDKs.<ref name=16soucek /><ref name=17-levine /> Activated p21 can bind cyclin D/CDK4 and render it incapable of phosphorylating pRb. PRb remains hypophosphorylated and binds E2F. E2F is unable to activate the transcription of cyclins involved in cell cycle progression, such as cyclin A and the cell cycle is arrested at G₁.<ref name=11-Pagano /><ref name=17-levine /> Cell cycle arrest allows the cell to repair DNA damage before the cell divides and passes damaged DNA to daughter cells.

==References== {{Reflist|35em}}

==External links== * [http://www.sdbonline.org/fly/newgene/cyclina1.htm ''Drosophila'' ''Cyclin A'' - The Interactive Fly] * {{MeshName|Cyclin+A}}

{{Cell cycle proteins}}

Category:Cell cycle Category:Proteins Category:Cell cycle regulators