Cyclin D2 Explained

G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 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 cycle. Cyclins function as regulators of cyclin-dependent kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors.^[2]

Clinical significance

Mutations in CCND2 are associated to megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.^[3]

Further reading

• Xiong Y, Menninger J, Beach D, Ward DC . Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins . Genomics . 13 . 3 . 575–84 . Jul 1992 . 1386336 . 10.1016/0888-7543(92)90127-E .
• Zhu W, Zhao M, Mattapally S, Chen S, Zhang J . CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Remuscularization of Injured Ventricle . Circulation Research . 122. 1. 88–96. October 2017 . 29018036. 10.1161/CIRCRESAHA.117.311504 . 5756126 .
• Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ . Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6 . Molecular and Cellular Biology . 15 . 5 . 2672–81 . May 1995 . 7739547 . 230497 . 10.1128/MCB.15.5.2672.
• Meyerson M, Harlow E . Identification of G1 kinase activity for cdk6, a novel cyclin D partner . Molecular and Cellular Biology . 14 . 3 . 2077–86 . Mar 1994 . 8114739 . 358568 . 10.1128/MCB.14.3.2077.
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Ewen ME, Sluss HK, Sherr CJ, Matsushime H, Kato J, Livingston DM . Functional interactions of the retinoblastoma protein with mammalian D-type cyclins . Cell . 73 . 3 . 487–97 . May 1993 . 8343202 . 10.1016/0092-8674(93)90136-E . 41911038 .
• Palmero I, Holder A, Sinclair AJ, Dickson C, Peters G . Cyclins D1 and D2 are differentially expressed in human B-lymphoid cell lines . Oncogene . 8 . 4 . 1049–54 . Apr 1993 . 8455931 .
• Brooks AR, Shiffman D, Chan CS, Brooks EE, Milner PG . Functional analysis of the human cyclin D2 and cyclin D3 promoters . The Journal of Biological Chemistry . 271 . 15 . 9090–9 . Apr 1996 . 8621559 . 10.1074/jbc.271.15.9090 . free .
• Hirai H, Sherr CJ . Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1 . Molecular and Cellular Biology . 16 . 11 . 6457–67 . Nov 1996 . 8887674 . 231647 . 10.1128/MCB.16.11.6457.
• Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA . Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis . Nature . 384 . 6608 . 470–4 . Dec 1996 . 8945475 . 10.1038/384470a0 . 1996Natur.384..470S . 4331964 .
• Kitagawa M, Higashi H, Jung HK, Suzuki-Takahashi I, Ikeda M, Tamai K, Kato J, Segawa K, Yoshida E, Nishimura S, Taya Y . The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2 . The EMBO Journal . 15 . 24 . 7060–9 . Dec 1996 . 9003781 . 452531 . 10.1002/j.1460-2075.1996.tb01097.x.
• 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 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Guidato S, McLoughlin DM, Grierson AJ, Miller CC . Cyclin D2 interacts with cdk-5 and modulates cellular cdk-5/p35 activity . Journal of Neurochemistry . 70 . 1 . 335–40 . Jan 1998 . 9422379 . 10.1046/j.1471-4159.1998.70010335.x . 23986161 . free .
• Gómez Lahoz E, Liegeois NJ, Zhang P, Engelman JA, Horner J, Silverman A, Burde R, Roussel MF, Sherr CJ, Elledge SJ, DePinho RA . Cyclin D- and E-dependent kinases and the p57(KIP2) inhibitor: cooperative interactions in vivo . Molecular and Cellular Biology . 19 . 1 . 353–63 . Jan 1999 . 9858559 . 83893 . 10.1128/mcb.19.1.353.
• Bartkova J, Rajpert-de Meyts E, Skakkebaek NE, Bartek J . D-type cyclins in adult human testis and testicular cancer: relation to cell type, proliferation, differentiation, and malignancy . The Journal of Pathology . 187 . 5 . 573–81 . Apr 1999 . 10398124 . 10.1002/(SICI)1096-9896(199904)187:5<573::AID-PATH289>3.0.CO;2-H . 9474072 .
• Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J, Eilers M . Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27 . The EMBO Journal . 18 . 19 . 5321–33 . Oct 1999 . 10508165 . 1171602 . 10.1093/emboj/18.19.5321 .
• Sansal I, Dupont E, Toru D, Evrard C, Rouget P . NPDC-1, a regulator of neural cell proliferation and differentiation, interacts with E2F-1, reduces its binding to DNA and modulates its transcriptional activity . Oncogene . 19 . 43 . 5000–9 . Oct 2000 . 11042687 . 10.1038/sj.onc.1203843 . 41370242 .
• Choi D, Lee EY, Yoon S, Hwang S, Yoon BK, Lee JH . Clinical correlation of cyclin D2 mRNA expression in human luteinized granulosa cells . Journal of Assisted Reproduction and Genetics . 17 . 10 . 574–9 . Nov 2000 . 11209538 . 3455455 . 10.1023/A:1026470825514 .
• Tanguay DA, Colarusso TP, Doughty C, Pavlovic-Ewers S, Rothstein TL, Chiles TC . Cutting edge: differential signaling requirements for activation of assembled cyclin D3-cdk4 complexes in B-1 and B-2 lymphocyte subsets . Journal of Immunology . 166 . 7 . 4273–7 . Apr 2001 . 11254678 . 10.4049/jimmunol.166.7.4273 . free .
• Choi D, Yoon S, Lee E, Hwang S, Yoon B, Lee J . The expression of pseudogene cyclin D2 mRNA in the human ovary may be a novel marker for decreased ovarian function associated with the aging process . Journal of Assisted Reproduction and Genetics . 18 . 2 . 110–3 . Feb 2001 . 11285977 . 3455561 . 10.1023/A:1026538826392 .

Notes and References

1. Inaba T, Matsushime H, Valentine M, Roussel MF, Sherr CJ, Look AT . Genomic organization, chromosomal localization, and independent expression of human cyclin D genes . Genomics . 13 . 3 . 565–74 . Jul 1992 . 1386335 . 10.1016/0888-7543(92)90126-D .
2. Web site: Entrez Gene: CCND2 cyclin D2.
3. Mirzaa GM, Parry DA, Fry AE, Giamanco KA, Schwartzentruber J, Vanstone M, Logan CV, Roberts N, Johnson CA, Singh S, Kholmanskikh SS, Adams C, Hodge RD, Hevner RF, Bonthron DT, Braun KP, Faivre L, Rivière JB, St-Onge J, Gripp KW, Mancini GM, Pang K, Sweeney E, van Esch H, Verbeek N, Wieczorek D, Steinraths M, Majewski J, Boycott KM, Pilz DT, Ross ME, Dobyns WB, Sheridan EG . De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome . Nature Genetics . 46 . 5 . 510–5 . May 2014 . 24705253 . 4004933 . 10.1038/ng.2948 .