Cyclin D3 Explained

G1/S-specific cyclin-D3 is a protein that in humans is encoded by the CCND3 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 CDK 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. The CDK4 activity associated with this cyclin was reported to be necessary for cell cycle progression through G₂ phase into mitosis after UV radiation.^[2]

Clinical significance

Mutations in CCND3 are implicated in cases of breast cancer.^[3]

Interactions

Cyclin D3 has been shown to interact with:

• AKAP8,^[4]
• CDC2L1,^[5]
• CDKN1B,
• CRABP2,
• Cyclin-dependent kinase 4,^{[4] [6] [7] [8]}
• Cyclin-dependent kinase 6,^{[7] [9]}
• EIF3K,^[10] and
• Retinoic acid receptor alpha.^[11]

See also

• Cyclin
• Cyclin D

Further reading

• Motokura T, Keyomarsi K, Kronenberg HM, Arnold A . Cloning and characterization of human cyclin D3, a cDNA closely related in sequence to the PRAD1/cyclin D1 proto-oncogene . The Journal of Biological Chemistry . 267 . 28 . 20412–20415 . October 1992 . 1383201 . 10.1016/S0021-9258(19)88717-3 . free .
• Xiong Y, Menninger J, Beach D, Ward DC . Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins . Genomics . 13 . 3 . 575–584 . July 1992 . 1386336 . 10.1016/0888-7543(92)90127-E .
• Motokura T, Yi HF, Kronenberg HM, McBride OW, Arnold A . Assignment of the human cyclin D3 gene (CCND3) to chromosome 6p----q13 . Cytogenetics and Cell Genetics . 61 . 1 . 5–7 . 1992 . 1387066 . 10.1159/000133359 .
• Matsuoka S, Yamaguchi M, Matsukage A . D-type cyclin-binding regions of proliferating cell nuclear antigen . The Journal of Biological Chemistry . 269 . 15 . 11030–11036 . April 1994 . 7908906 . 10.1016/S0021-9258(19)78087-9 . free .
• Meyerson M, Harlow E . Identification of G1 kinase activity for cdk6, a novel cyclin D partner . Molecular and Cellular Biology . 14 . 3 . 2077–2086 . March 1994 . 8114739 . 358568 . 10.1128/MCB.14.3.2077 .
• Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA . Physical interaction of the retinoblastoma protein with human D cyclins . Cell . 73 . 3 . 499–511 . May 1993 . 8490963 . 10.1016/0092-8674(93)90137-F . 24708871 .
• 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 . 9090–9099 . April 1996 . 8621559 . 10.1074/jbc.271.15.9090 . free .
• Tiefenbrun N, Melamed D, Levy N, Resnitzky D, Hoffman I, Reed SI, Kimchi A . Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest . Molecular and Cellular Biology . 16 . 7 . 3934–3944 . July 1996 . 8668211 . 231390 . 10.1128/MCB.16.7.3934 .
• Hirai H, Sherr CJ . Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1 . Molecular and Cellular Biology . 16 . 11 . 6457–6467 . November 1996 . 8887674 . 231647 . 10.1128/MCB.16.11.6457 .
• Doglioni C, Chiarelli C, Macrí E, Dei Tos AP, Meggiolaro E, Dalla Palma P, Barbareschi M . Cyclin D3 expression in normal, reactive and neoplastic tissues . The Journal of Pathology . 185 . 2 . 159–166 . June 1998 . 9713342 . 10.1002/(SICI)1096-9896(199806)185:2<159::AID-PATH73>3.0.CO;2-0 . 38572590 .
• 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 . 353–363 . January 1999 . 9858559 . 83893 . 10.1128/mcb.19.1.353 .
• Gabrielli BG, Sarcevic B, Sinnamon J, Walker G, Castellano M, Wang XQ, Ellem KA . A cyclin D-Cdk4 activity required for G2 phase cell cycle progression is inhibited in ultraviolet radiation-induced G2 phase delay . The Journal of Biological Chemistry . 274 . 20 . 13961–13969 . May 1999 . 10318807 . 10.1074/jbc.274.20.13961 . free .
• Zhang Q, Wang X, Wolgemuth DJ . Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis . Endocrinology . 140 . 6 . 2790–2800 . June 1999 . 10342870 . 10.1210/endo.140.6.6756 . free .
• 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 . 573–581 . April 1999 . 10398124 . 10.1002/(SICI)1096-9896(199904)187:5<573::AID-PATH289>3.0.CO;2-H . 9474072 .
• Jones CJ, Kipling D, Morris M, Hepburn P, Skinner J, Bounacer A, Wyllie FS, Ivan M, Bartek J, Wynford-Thomas D, Bond JA . Evidence for a telomere-independent "clock" limiting RAS oncogene-driven proliferation of human thyroid epithelial cells . Molecular and Cellular Biology . 20 . 15 . 5690–5699 . August 2000 . 10891505 . 86042 . 10.1128/MCB.20.15.5690-5699.2000 .
• 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 . 5000–5009 . October 2000 . 11042687 . 10.1038/sj.onc.1203843 . free .
• Fink JR, LeBien TW . Novel expression of cyclin-dependent kinase inhibitors in human B-cell precursors . Experimental Hematology . 29 . 4 . 490–498 . April 2001 . 11301189 . 10.1016/S0301-472X(01)00619-1 . free .
• Lin J, Jinno S, Okayama H . Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence . Oncogene . 20 . 16 . 2000–2009 . April 2001 . 11360184 . 10.1038/sj.onc.1204375 . free .
• Bartkova J, Thullberg M, Slezak P, Jaramillo E, Rubio C, Thomassen LH, Bartek J . Aberrant expression of G1-phase cell cycle regulators in flat and exophytic adenomas of the human colon . Gastroenterology . 120 . 7 . 1680–1688 . June 2001 . 11375949 . 10.1053/gast.2001.24880 . free .

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 . 565–574 . July 1992 . 1386335 . 10.1016/0888-7543(92)90126-D .
2. Web site: Entrez Gene: CCND3 cyclin D3.
3. Comprehensive molecular portraits of human breast tumours . Nature . 490 . 7418 . 61–70 . October 2012 . 23000897 . 3465532 . 10.1038/nature11412 . 2012Natur.490...61T . Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, Fulton LL, Dooling DJ, Ding L, Mardis ER, Ally A, Balasundaram M, Butterfield YS, Carlsen R, Carter C, Chu A, Chuah E, Chun HE, Coope RJ, Dhalla N, Guin R, Hirst C, Hirst M, Holt RA, Lee D, Li HI, Mayo M, Moore RA, Mungall AJ . Cancer Genome Atlas Network .
4. Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I . A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95 . The Biochemical Journal . 378 . Pt 2 . 673–679 . March 2004 . 14641107 . 1223988 . 10.1042/BJ20031765 .
5. Zhang S, Cai M, Zhang S, Xu S, Chen S, Chen X, Chen C, Gu J . Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3 . The Journal of Biological Chemistry . 277 . 38 . 35314–35322 . September 2002 . 12082095 . 10.1074/jbc.M202179200 . free .
6. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .
7. Lin J, Jinno S, Okayama H . Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence . Oncogene . 20 . 16 . 2000–2009 . April 2001 . 11360184 . 10.1038/sj.onc.1204375 . free .
8. Zhang Q, Wang X, Wolgemuth DJ . Developmentally regulated expression of cyclin D3 and its potential in vivo interacting proteins during murine gametogenesis . Endocrinology . 140 . 6 . 2790–2800 . June 1999 . 10342870 . 10.1210/endo.140.6.6756 . free .
9. Meyerson M, Harlow E . Identification of G1 kinase activity for cdk6, a novel cyclin D partner . Molecular and Cellular Biology . 14 . 3 . 2077–2086 . March 1994 . 8114739 . 358568 . 10.1128/MCB.14.3.2077 .
10. Shen X, Yang Y, Liu W, Sun M, Jiang J, Zong H, Gu J . Identification of the p28 subunit of eukaryotic initiation factor 3(eIF3k) as a new interaction partner of cyclin D3 . FEBS Letters . 573 . 1–3 . 139–146 . August 2004 . 15327989 . 10.1016/j.febslet.2004.07.071 . 16005938 . free . 2004FEBSL.573..139S .
11. Despouy G, Bastie JN, Deshaies S, Balitrand N, Mazharian A, Rochette-Egly C, Chomienne C, Delva L . Cyclin D3 is a cofactor of retinoic acid receptors, modulating their activity in the presence of cellular retinoic acid-binding protein II . The Journal of Biological Chemistry . 278 . 8 . 6355–6362 . February 2003 . 12482873 . 10.1074/jbc.M210697200 . free .