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 . J. Biol. Chem. . 267 . 28 . 20412–5 . 1992 . 10.1016/S0021-9258(19)88717-3 . 1383201 . 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 . 575–84 . 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 . Cytogenet. Cell Genet. . 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 . J. Biol. Chem. . 269 . 15 . 11030–6 . 1994 . 10.1016/S0021-9258(19)78087-9 . 7908906 . free .
• Meyerson M, Harlow E . Identification of G1 kinase activity for cdk6, a novel cyclin D partner . Mol. Cell. Biol. . 14 . 3 . 2077–86 . 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 . 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 . J. Biol. Chem. . 271 . 15 . 9090–9 . 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 . Mol. Cell. Biol. . 16 . 7 . 3934–44 . 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 . Mol. Cell. Biol. . 16 . 11 . 6457–67 . 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 . J. Pathol. . 185 . 2 . 159–66 . 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 . Mol. Cell. Biol. . 19 . 1 . 353–63 . 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 . J. Biol. Chem. . 274 . 20 . 13961–9 . 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 . 2790–800 . 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 . J. Pathol. . 187 . 5 . 573–81 . 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 . Mol. Cell. Biol. . 20 . 15 . 5690–9 . 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 . 5000–9 . 2000 . 11042687 . 10.1038/sj.onc.1203843 . free .
• Fink JR, LeBien TW . Novel expression of cyclin-dependent kinase inhibitors in human B-cell precursors . Exp. Hematol. . 29 . 4 . 490–8 . 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 . 2000–9 . 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 . 1680–8 . 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 . 565–74 . August 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 . 2012 . 23000897 . 3465532 . 10.1038/nature11412 . Koboldt . Daniel C. . Fulton . Robert S. . McLellan . Michael D. . Schmidt . Heather . Kalicki-Veizer . Joelle . McMichael . Joshua F. . Fulton . Lucinda L. . Dooling . David J. . Ding . Li . Mardis . Elaine R. . Wilson . Richard K. . Ally . Adrian . Balasundaram . Miruna . Butterfield . Yaron S. N. . Carlsen . Rebecca . Carter . Candace . Chu . Andy . Chuah . Eric . Chun . Hye-Jung E. . Coope . Robin J. N. . Dhalla . Noreen . Guin . Ranabir . Hirst . Carrie . Hirst . Martin . Holt . Robert A. . Lee . Darlene . Li . Haiyan I. . Mayo . Michael . Moore . Richard A. . Mungall . Andrew J. . 2012Natur.490...61T . 29 .
4. Arsenijevic T, Degraef C, Dumont JE, Roger PP, Pirson I . A novel partner for D-type cyclins: protein kinase A-anchoring protein AKAP95 . Biochem. J. . 378 . Pt 2 . 673–9 . 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 . J. Biol. Chem. . 277 . 38 . 35314–22 . 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 . 1173–8 . 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
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 . 2000–9 . 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 . 2790–800 . 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 . Mol. Cell. Biol. . 14 . 3 . 2077–86 . 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 Lett. . 573 . 1–3 . 139–46 . 2004 . 15327989 . 10.1016/j.febslet.2004.07.071 . 16005938 . free .
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 . J. Biol. Chem. . 278 . 8 . 6355–62 . 2003 . 12482873 . 10.1074/jbc.M210697200 . free .