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Gene Review

Ccnd2  -  cyclin D2

Mus musculus

Synonyms: 2600016F06Rik, AI256817, BF642806, C86853, Cyl-2, ...
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Disease relevance of Ccnd2


High impact information on Ccnd2

  • Pitx2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes that prove necessary for Cyclin D2 gene induction [6].
  • To directly test the ability of each D-cyclin to drive development of various lineages, we generated mice expressing only cyclin D1, or only cyclin D2, or only cyclin D3 [1].
  • Ectopic expression of cyclin D2 in rodent fibroblasts, either alone or together with exogenous cdk4, shortened their G0- to S-phase interval and reduced their serum dependency, but cyclin D2 alone did not alter cell size significantly [7].
  • To address the mechanism underlying the varied proliferative responses of B-1 and B-2 cells, we evaluated the expression and activity of the G1 cell cycle regulator, cyclin D2, and its associated cyclin-dependent kinases (Cdks) [8].
  • These results strongly suggest that the rapid induction of cyclin D2 by a normally nonmitogenic phorbol ester stimulus is responsible for B-1 cell progression through G1 phase [8].

Chemical compound and disease context of Ccnd2

  • Treatment with the methyl transferase inhibitor 5'-aza-2'-deoxycytidine (AZAdC) increased expression of cyclin D2 and p27 in GH3 and GHRH-CL1 pituitary tumor cells [9].
  • Bisulfite genomic sequencing showed that the normally unmethylated cytosines of the p27 gene in normal pituitary (NP) were extensively methylated in GH3 and GHRH-CL1 cells, but not in AtT 20, alphaT3-1 and LbetaT2 cells; but cyclin D2 was extensively inactivated in various pituitary tumor cell lines by increased DNA methylation [9].

Biological context of Ccnd2


Anatomical context of Ccnd2


Associations of Ccnd2 with chemical compounds

  • These findings are further confirmed by studies showing that specific pharmacological inhibitors of Btk (LFM-A13), PI3-K (LY294002 and Wortmannin) and PLCgamma (U73122) also block cyclin D2 expression and S phase entry following BCR stimulation, as well as triggering apoptosis [14].
  • Consistent with this, we also showed that the BCR-mediated cyclin D2 induction could be abolished by pretreatment of resting B cells with specific inhibitors of capacitative Ca(2+) entry (SK&F 96365) or PKC (Gö6850) [14].
  • In small resting (G0) B cells, costimulation with PMA and ionomycin, but not PMA or ionomycin alone, induces cyclin D2 expression and cell-cycle progression [14].
  • Cyclin D2 was translocated into the nucleus in response to E2 in the cyclin D1-/- mice to a much greater degree than in wild-type mice [15].
  • However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age [16].

Physical interactions of Ccnd2


Regulatory relationships of Ccnd2


Other interactions of Ccnd2

  • To study the cell cycle-regulatory factors involved in ovarian, testicular, and adrenal tumor development in vivo, we have bred Inhalpha mutant mice to mice with targeted disruptions of the p27 and cyclin D2 genes [23].
  • We found that double-knockout females lacking cyclin D2 and Inhalpha lived longer than mice lacking inhibins alone; the majority of these double-knockout mice lived longer than 17 wk, as opposed to inhibin alpha single-knockout females with 50% survival at between 12 and 13 wk of age [23].
  • In these studies, 4-1BB costimulation was shown to increase cyclin D2, D3, and E expression, and concomitantly down-regulate the expression of the cyclin-dependent kinase inhibitor p27(kip1) [12].
  • Whereas immature stage B cells increased expression of cyclin D2 and cdk4 after anti-IgM stimulation, unlike mature stage B cells they failed to express cyclin E and cdk2 [24].
  • Requirement for a hsp90 chaperone-dependent MEK1/2-ERK pathway for B cell antigen receptor-induced cyclin D2 expression in mature B lymphocytes [25].
  • We conclude that cyclin D3 and cyclin D2 play opposite roles in mouse skin tumor development and that the suppressive activity of cyclin D3 is associated with cyclin D2 downregulation [26].

Analytical, diagnostic and therapeutic context of Ccnd2


  1. Development of mice expressing a single D-type cyclin. Ciemerych, M.A., Kenney, A.M., Sicinska, E., Kalaszczynska, I., Bronson, R.T., Rowitch, D.H., Gardner, H., Sicinski, P. Genes Dev. (2002) [Pubmed]
  2. Cyclin D2 overexpression in transgenic mice induces thymic and epidermal hyperplasia whereas cyclin D3 expression results only in epidermal hyperplasia. Rodriguez-Puebla, M.L., LaCava, M., Miliani De Marval, P.L., Jorcano, J.L., Richie, E.R., Conti, C.J. Am. J. Pathol. (2000) [Pubmed]
  3. Critical role for cyclin D2 in BCR/ABL-induced proliferation of hematopoietic cells. Jena, N., Deng, M., Sicinska, E., Sicinski, P., Daley, G.Q. Cancer Res. (2002) [Pubmed]
  4. Identification of a novel gene, Vin-1, in murine leukemia virus-induced T-cell leukemias by provirus insertional mutagenesis. Tremblay, P.J., Kozak, C.A., Jolicoeur, P. J. Virol. (1992) [Pubmed]
  5. Gris1, a new common integration site in Graffi murine leukemia virus-induced leukemias: overexpression of a truncated cyclin D2 due to alternative splicing. Denicourt, C., Kozak, C.A., Rassart, E. J. Virol. (2003) [Pubmed]
  6. Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development. Kioussi, C., Briata, P., Baek, S.H., Rose, D.W., Hamblet, N.S., Herman, T., Ohgi, K.A., Lin, C., Gleiberman, A., Wang, J., Brault, V., Ruiz-Lozano, P., Nguyen, H.D., Kemler, R., Glass, C.K., Wynshaw-Boris, A., Rosenfeld, M.G. Cell (2002) [Pubmed]
  7. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Quelle, D.E., Ashmun, R.A., Shurtleff, S.A., Kato, J.Y., Bar-Sagi, D., Roussel, M.F., Sherr, C.J. Genes Dev. (1993) [Pubmed]
  8. Early induction of cyclin D2 expression in phorbol ester-responsive B-1 lymphocytes. Tanguay, D.A., Colarusso, T.P., Pavlovic, S., Irigoyen, M., Howard, R.G., Bartek, J., Chiles, T.C., Rothstein, T.L. J. Exp. Med. (1999) [Pubmed]
  9. Aberrant DNA methylation of cyclin D2 and p27 genes in rodent pituitary tumor cell lines correlates with specific gene expression. Qian, X., Jin, L., Lloyd, R.V. Endocr. Pathol. (2000) [Pubmed]
  10. The critical role of cyclin D2 in adult neurogenesis. Kowalczyk, A., Filipkowski, R.K., Rylski, M., Wilczynski, G.M., Konopacki, F.A., Jaworski, J., Ciemerych, M.A., Sicinski, P., Kaczmarek, L. J. Cell Biol. (2004) [Pubmed]
  11. Cyclin D3 compensates for loss of cyclin D2 in mouse B-lymphocytes activated via the antigen receptor and CD40. Lam, E.W., Glassford, J., Banerji, L., Thomas, N.S., Sicinski, P., Klaus, G.G. J. Biol. Chem. (2000) [Pubmed]
  12. 4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1. Lee, H.W., Nam, K.O., Park, S.J., Kwon, B.S. Eur. J. Immunol. (2003) [Pubmed]
  13. Phosphatidylinositol 3-kinase-dependent mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 and NF-kappa B signaling pathways are required for B cell antigen receptor-mediated cyclin D2 induction in mature B cells. Piatelli, M.J., Wardle, C., Blois, J., Doughty, C., Schram, B.R., Rothstein, T.L., Chiles, T.C. J. Immunol. (2004) [Pubmed]
  14. BCR targets cyclin D2 via Btk and the p85alpha subunit of PI3-K to induce cell cycle progression in primary mouse B cells. Glassford, J., Soeiro, I., Skarell, S.M., Banerji, L., Holman, M., Klaus, G.G., Kadowaki, T., Koyasu, S., Lam, E.W. Oncogene (2003) [Pubmed]
  15. Cyclin D2 compensates for the loss of cyclin D1 in estrogen-induced mouse uterine epithelial cell proliferation. Chen, B., Pollard, J.W. Mol. Endocrinol. (2003) [Pubmed]
  16. Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. Kushner, J.A., Ciemerych, M.A., Sicinska, E., Wartschow, L.M., Teta, M., Long, S.Y., Sicinski, P., White, M.F. Mol. Cell. Biol. (2005) [Pubmed]
  17. Mechanisms of cell cycle arrest in response to TGF-beta in progestin-dependent and -independent growth of mammary tumors. Salatino, M., Labriola, L., Schillaci, R., Charreau, E.H., Elizalde, P.V. Exp. Cell Res. (2001) [Pubmed]
  18. Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression. Dey, A., She, H., Kim, L., Boruch, A., Guris, D.L., Carlberg, K., Sebti, S.M., Woodley, D.T., Imamoto, A., Li, W. Mol. Biol. Cell (2000) [Pubmed]
  19. Proliferation-independent induction of macrophage cyclin D2, and repression of cyclin D1, by lipopolysaccharide. Vadiveloo, P.K., Vairo, G., Royston, A.K., Novak, U., Hamilton, J.A. J. Biol. Chem. (1998) [Pubmed]
  20. Functional analysis of cyclin D2 and p27(Kip1) in cyclin D2 transgenic mouse mammary gland during development. Kong, G., Chua, S.S., Yijun, Y., Kittrell, F., Moraes, R.C., Medina, D., Said, T.K. Oncogene (2002) [Pubmed]
  21. Ras and Myc can drive oncogenic cell proliferation through individual D-cyclins. Yu, Q., Ciemerych, M.A., Sicinski, P. Oncogene (2005) [Pubmed]
  22. Evidence for a direct correlation between c-Jun NH2 terminal kinase 1 activation, cyclin D2 expression, and G(1)/S phase transition in the murine hybridoma 7TD1 cells. Turchi, L., Loubat, A., Rochet, N., Rossi, B., Ponzio, G. Exp. Cell Res. (2000) [Pubmed]
  23. Cyclin D2 and p27 are tissue-specific regulators of tumorigenesis in inhibin alpha knockout mice. Burns, K.H., Agno, J.E., Sicinski, P., Matzuk, M.M. Mol. Endocrinol. (2003) [Pubmed]
  24. Immature stage B cells enter but do not progress beyond the early G1 phase of the cell cycle in response to antigen receptor signaling. Carman, J.A., Wechsler-Reya, R.J., Monroe, J.G. J. Immunol. (1996) [Pubmed]
  25. Requirement for a hsp90 chaperone-dependent MEK1/2-ERK pathway for B cell antigen receptor-induced cyclin D2 expression in mature B lymphocytes. Piatelli, M.J., Doughty, C., Chiles, T.C. J. Biol. Chem. (2002) [Pubmed]
  26. Cyclin D2 and cyclin D3 play opposite roles in mouse skin carcinogenesis. Rojas, P., Cadenas, M.B., Lin, P.C., Benavides, F., Conti, C.J., Rodriguez-Puebla, M.L. Oncogene (2007) [Pubmed]
  27. Distinct patterns of expression of the D-type cyclins during testicular development in the mouse. Ravnik, S.E., Rhee, K., Wolgemuth, D.J. Dev. Genet. (1995) [Pubmed]
  28. Androgen regulation of stage-dependent cyclin D2 expression in Sertoli cells suggests a role in modulating androgen action on spermatogenesis. Tan, K.A., Turner, K.J., Saunders, P.T., Verhoeven, G., De Gendt, K., Atanassova, N., Sharpe, R.M. Biol. Reprod. (2005) [Pubmed]
  29. Temporal patterns of gene expression of G1-S cyclins and cdks during the first and second mitotic cell cycles in mouse embryos. Moore, G.D., Ayabe, T., Kopf, G.S., Schultz, R.M. Mol. Reprod. Dev. (1996) [Pubmed]
  30. Increased expression of cyclin D2 during multiple states of growth arrest in primary and established cells. Meyyappan, M., Wong, H., Hull, C., Riabowol, K.T. Mol. Cell. Biol. (1998) [Pubmed]
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