Cyclin A1 Explained

Cyclin-A1 is a protein that in humans is encoded by the CCNA1 gene.^[1]

Function

The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell division cycle. Cyclins function as activating subunits of enzymatic complex together with cyclin-dependent kinases (CDKs). Different cyclins exhibit distinct expression and degradation patterns that contribute to the temporal coordination of cell cycle events. Cyclin A1 was shown to be expressed in testis and brain, as well as in several leukemic cell lines, and is thought to primarily function in the control of meiosis. This cyclin binds both Cdk1 and Cdk2 kinases, which give two distinct kinase activities, one appearing in S phase, the other in G2, and thus regulate separate functions in cell cycle. This cyclin was found to bind to important cell cycle regulators, such as Rb family proteins, transcription factor E2F1, and the Kip/Cip family of CDK-inhibitor proteins.^[2]

Interactions

Cyclin-A1 interacts with:

• CDC20,^[3]
• Cyclin-dependent kinase 2,^{[4] [5] [6]}
• E2F1,^[7]
• GNB2L1,
• GPS2,^[8]
• MYBL2,^[5] and
• Retinoblastoma protein.^[7]

Further reading

• Hall M, Bates S, Peters G . Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins . Oncogene . 11 . 8 . 1581–1588 . 1995 . 7478582 .
• Xu M, Sheppard KA, Peng CY, Yee AS, Piwnica-Worms H . 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 . 7969176 . 359381 . 10.1128/MCB.14.12.8420.
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• O'Connor PM, Ferris DK, Pagano M, Draetta G, Pines J, Hunter T, Longo DL, Kohn KW . G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B1/cdc2-kinase complexes differently . J. Biol. Chem. . 268 . 11 . 8298–8308 . 1993 . 10.1016/S0021-9258(18)53096-9 . 8463339 . free .
• Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF, Wolgemuth DJ, Carrington M . A distinct cyclin A is expressed in germ cells in the mouse . Development . 122 . 1 . 53–64 . 1996 . 10.1242/dev.122.1.53 . 8565853 .
• Wang H, Shao N, Ding QM, Cui J, Reddy ES, Rao VN . BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases . Oncogene . 15 . 2 . 143–157 . 1997 . 9244350 . 10.1038/sj.onc.1201252 . 11930784 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Liu D, Matzuk MM, Sung WK, Guo Q, Wang P, Wolgemuth DJ . Cyclin A1 is required for meiosis in the male mouse . Nat. Genet. . 20 . 4 . 377–380 . 1998 . 9843212 . 10.1038/3855 . 23356816 .
• Yang R, Müller C, Huynh V, Fung YK, Yee AS, Koeffler HP . Functions of cyclin A1 in the cell cycle and its interactions with transcription factor E2F-1 and the Rb family of proteins . Mol. Cell. Biol. . 19 . 3 . 2400–2407 . 1999 . 10022926 . 84032 . 10.1128/mcb.19.3.2400.
• Ravnik SE, Wolgemuth DJ . Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage . Dev. Biol. . 207 . 2 . 408–418 . 1999 . 10068472 . 10.1006/dbio.1998.9156 . free .
• Yang R, Nakamaki T, Lübbert M, Said J, Sakashita A, Freyaldenhoven BS, Spira S, Huynh V, Müller C, Koeffler HP . Cyclin A1 expression in leukemia and normal hematopoietic cells . Blood . 93 . 6 . 2067–2074 . 1999 . 10068680 .
• Müller C, Yang R, Beck-von-Peccoz L, Idos G, Verbeek W, Koeffler HP . Cloning of the cyclin A1 genomic structure and characterization of the promoter region. GC boxes are essential for cell cycle-regulated transcription of the cyclin A1 gene . J. Biol. Chem. . 274 . 16 . 11220–11228 . 1999 . 10196209 . 10.1074/jbc.274.16.11220 . free .
• Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM . BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site . Mol. Cell. Biol. . 19 . 7 . 4843–4854 . 1999 . 10373534 . 84283 . 10.1128/MCB.19.7.4843.
• Brown NR, Noble ME, Endicott JA, Johnson LN . The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases . Nat. Cell Biol. . 1 . 7 . 438–443 . 1999 . 10559988 . 10.1038/15674 . 17988582 .
• Liu D, Liao C, Wolgemuth DJ . A role for cyclin A1 in the activation of MPF and G2-M transition during meiosis of male germ cells in mice . Dev. Biol. . 224 . 2 . 388–400 . 2000 . 10926775 . 10.1006/dbio.2000.9776 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Res. . 10 . 11 . 1788–1795 . 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Müller-Tidow C, Bornemann C, Diederichs S, Westermann A, Klümpen S, Zuo P, Wang W, Berdel WE, Serve H . Analyses of the genomic methylation status of the human cyclin A1 promoter by a novel real-time PCR-based methodology . FEBS Lett. . 490 . 1–2 . 75–78 . 2001 . 11172814 . 10.1016/S0014-5793(01)02128-7 . free .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Rep. . 1 . 3 . 287–292 . 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Müller-Tidow C, Wang W, Idos GE, Diederichs S, Yang R, Readhead C, Berdel WE, Serve H, Saville M, Watson R, Koeffler HP . Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function . Blood . 97 . 7 . 2091–2097 . 2001 . 11264176 . 10.1182/blood.V97.7.2091 . free .

Notes and References

1. Yang R, Morosetti R, Koeffler HP . Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines . Cancer Res. . 57 . 5 . 913–920 . March 1997 . 9041194 .
2. Web site: Entrez Gene: CCNA1 cyclin A1.
3. Ohtoshi A, Maeda T, Higashi H, Ashizawa S, Hatakeyama M . Human p55(CDC)/Cdc20 associates with cyclin A and is phosphorylated by the cyclin A-Cdk2 complex . Biochem. Biophys. Res. Commun. . 268 . 2 . 530–534 . February 2000 . 10679238 . 10.1006/bbrc.2000.2167 .
4. Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF, Wolgemuth DJ, Carrington M . A distinct cyclin A is expressed in germ cells in the mouse . Development . 122 . 1 . 53–64 . January 1996 . 10.1242/dev.122.1.53 . 8565853 .
5. Müller-Tidow C, Wang W, Idos GE, Diederichs S, Yang R, Readhead C, Berdel WE, Serve H, Saville M, Watson R, Koeffler HP . Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function . Blood . 97 . 7 . 2091–2097 . April 2001 . 11264176 . 10.1182/blood.v97.7.2091. free .
6. Brown NR, Noble ME, Endicott JA, Johnson LN . The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases . Nat. Cell Biol. . 1 . 7 . 438–443 . November 1999 . 10559988 . 10.1038/15674 . 17988582 .
7. Yang R, Müller C, Huynh V, Fung YK, Yee AS, Koeffler HP . Functions of cyclin A1 in the cell cycle and its interactions with transcription factor E2F-1 and the Rb family of proteins . Mol. Cell. Biol. . 19 . 3 . 2400–2407 . March 1999 . 10022926 . 84032 . 10.1128/mcb.19.3.2400.
8. Diederichs S, Bäumer N, Ji P, Metzelder SK, Idos GE, Cauvet T, Wang W, Möller M, Pierschalski S, Gromoll J, Schrader MG, Koeffler HP, Berdel WE, Serve H, Müller-Tidow C . Identification of interaction partners and substrates of the cyclin A1-CDK2 complex . J. Biol. Chem. . 279 . 32 . 33727–33741 . August 2004 . 15159402 . 10.1074/jbc.M401708200 . free .