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Gene Review

CCND2  -  cyclin D2

Homo sapiens

Synonyms: G1/S-specific cyclin-D2, KIAK0002, MPPH3
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Disease relevance of CCND2


High impact information on CCND2

  • Introduction of cyclin D2 and Rb into the Rb-deficient cell line SAOS-2 led to overt Rb hyperphosphorylation, whereas Rb, expressed alone or together with cyclin D1, remained unphosphorylated [6].
  • Cyclin D2-dependent phosphorylation inhibited its binding to the transcription factor E2F and reversed the Rb G1 exit block in the cell cycle [6].
  • Cyclin D2-deficient females are sterile owing to the inability of ovarian granulosa cells to proliferate normally in response to follicle-stimulating hormone (FSH), whereas mutant males display hypoplastic testes [7].
  • Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis [7].
  • To investigate why mammalian cells need three distinct D-type cyclins, we have generated mice bearing a disrupted cyclin D2 gene by using gene targeting in embryonic stem cells [7].

Chemical compound and disease context of CCND2


Biological context of CCND2


Anatomical context of CCND2

  • In order to evaluate dysregulation in T-ALL with respect to normal T-cell differentiation, we analyzed CCND2 expression in normal purified human thymic subpopulations [5].
  • Among the candidate amplified genes mapped to 12p, expression of the cyclin D2 gene (CCND2) was deregulated in a panel of GCT cell lines, with the relative level of steady-state mRNA and protein inversely correlated with the pattern of differentiation characteristic of the cell line [17].
  • The results indicate that each growth factor involves a separate mechanism to maintain an effective level of CCND2 in granulosa cells for the activation of CDK4 and induction of DNA synthesis [18].
  • In myeloid cell lines, the levels of cyclin D1 expression varied and never exceeded the sum of cyclin D2 and D3 levels [19].
  • Therefore, cyclin D2 preferentially activated Cdk2 in breast epithelial cells [20].

Associations of CCND2 with chemical compounds


Physical interactions of CCND2

  • FSH stimulation results in the formation and activation of the cyclin D2/CDK4 complex leading to DNA synthesis [25].
  • Mutation of the CREB-binding site reduced cyclin D2 promoter activity 5-10-fold [26].

Enzymatic interactions of CCND2

  • GSK3beta and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells [27].

Regulatory relationships of CCND2


Other interactions of CCND2

  • Adenomas showed elevated expression of cyclin D1 and pRB, frequent induction of cyclin D2, and absence of p16 [32].
  • In addition, the cyclin D2 partner CDK4 was increased in 41% (21 of 51) of all tumors by a factor of 6, most strongly in embryonal carcinomas [33].
  • Some genes important in the control of the G(1)-S cell cycle checkpoint G(1)-S, i.e., cyclin-dependent kinases 2 and 4, cyclin D2 are located on this chromosomal region [33].
  • Survival curves showed CCND2 (especially cytoplasmic staining) and CDK4 positivity to be associated with a poor prognosis and CCNE positivity with a better prognosis [34].
  • Although the high preoperative serum prostate-specific antigen (PSA) group did not have significantly greater methylation frequency, methylation of Cyclin D2 had higher mean PSA value [35].

Analytical, diagnostic and therapeutic context of CCND2


  1. Molecular characterization of 12p abnormalities in hematologic malignancies: deletion of KIP1, rearrangement of TEL, and amplification of CCND2. Höglund, M., Johansson, B., Pedersen-Bjergaard, J., Marynen, P., Mitelman, F. Blood (1996) [Pubmed]
  2. Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. Agnelli, L., Bicciato, S., Mattioli, M., Fabris, S., Intini, D., Verdelli, D., Baldini, L., Morabito, F., Callea, V., Lombardi, L., Neri, A. J. Clin. Oncol. (2005) [Pubmed]
  3. Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. Büschges, R., Weber, R.G., Actor, B., Lichter, P., Collins, V.P., Reifenberger, G. Brain Pathol. (1999) [Pubmed]
  4. Study on the role of G1 cyclins in Epstein-Barr virus-associated human lymphomas maintained in severe combined immune deficiency (SCID) mice. Murai, Y., Dobashi, Y., Okada, E., Ishizawa, S., Shiota, M., Mori, S., Takano, Y. Int. J. Cancer (2001) [Pubmed]
  5. Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias. Clappier, E., Cuccuini, W., Cayuela, J.M., Vecchione, D., Baruchel, A., Dombret, H., Sigaux, F., Soulier, J. Leukemia (2006) [Pubmed]
  6. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Ewen, M.E., Sluss, H.K., Sherr, C.J., Matsushime, H., Kato, J., Livingston, D.M. Cell (1993) [Pubmed]
  7. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Sicinski, P., Donaher, J.L., Geng, Y., Parker, S.B., Gardner, H., Park, M.Y., Robker, R.L., Richards, J.S., McGinnis, L.K., Biggers, J.D., Eppig, J.J., Bronson, R.T., Elledge, S.J., Weinberg, R.A. Nature (1996) [Pubmed]
  8. Mitoxantrone mediates demethylation and reexpression of cyclin d2, estrogen receptor and 14.3.3sigma in breast cancer cells. Parker, B.S., Cutts, S.M., Nudelman, A., Rephaeli, A., Phillips, D.R., Sukumar, S. Cancer Biol. Ther. (2003) [Pubmed]
  9. Overexpression of c-Maf contributes to T-cell lymphoma in both mice and human. Morito, N., Yoh, K., Fujioka, Y., Nakano, T., Shimohata, H., Hashimoto, Y., Yamada, A., Maeda, A., Matsuno, F., Hata, H., Suzuki, A., Imagawa, S., Mitsuya, H., Esumi, H., Koyama, A., Yamamoto, M., Mori, N., Takahashi, S. Cancer Res. (2006) [Pubmed]
  10. Egr1 promotes growth and survival of prostate cancer cells. Identification of novel Egr1 target genes. Virolle, T., Krones-Herzig, A., Baron, V., De Gregorio, G., Adamson, E.D., Mercola, D. J. Biol. Chem. (2003) [Pubmed]
  11. Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues. Matsubayashi, H., Sato, N., Fukushima, N., Yeo, C.J., Walter, K.M., Brune, K., Sahin, F., Hruban, R.H., Goggins, M. Clin. Cancer Res. (2003) [Pubmed]
  12. The mitogenic signaling pathway for fibroblast growth factor-2 involves the tyrosine phosphorylation of cyclin D2 in MCF-7 human breast cancer cells. Vercoutter-Edouart, A., Lemoine, J., Smart, C.E., Nurcombe, V., Boilly, B., Peyrat, J., Hondermarck, H. FEBS Lett. (2000) [Pubmed]
  13. Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling. Fu, K., Weisenburger, D.D., Greiner, T.C., Dave, S., Wright, G., Rosenwald, A., Chiorazzi, M., Iqbal, J., Gesk, S., Siebert, R., De Jong, D., Jaffe, E.S., Wilson, W.H., Delabie, J., Ott, G., Dave, B.J., Sanger, W.G., Smith, L.M., Rimsza, L., Braziel, R.M., Müller-Hermelink, H.K., Campo, E., Gascoyne, R.D., Staudt, L.M., Chan, W.C. Blood (2005) [Pubmed]
  14. Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins. Xiong, Y., Menninger, J., Beach, D., Ward, D.C. Genomics (1992) [Pubmed]
  15. DNA hypermethylation in breast cancer and its association with clinicopathological features. Li, S., Rong, M., Iacopetta, B. Cancer Lett. (2006) [Pubmed]
  16. Identification of multiple cell cycle regulatory functions of p57Kip2 in human T lymphocytes. Li, G., Domenico, J., Lucas, J.J., Gelfand, E.W. J. Immunol. (2004) [Pubmed]
  17. Aberrant expression of cyclin D2 is an early event in human male germ cell tumorigenesis. Houldsworth, J., Reuter, V., Bosl, G.J., Chaganti, R.S. Cell Growth Differ. (1997) [Pubmed]
  18. Transforming growth factor B1 stimulated DNA synthesis in the granulosa cells of preantral follicles: negative interaction with epidermal growth factor. Yang, P., Roy, S.K. Biol. Reprod. (2006) [Pubmed]
  19. Detection of cyclin D1 (bcl-1, PRAD1) overexpression by a simple competitive reverse transcription-polymerase chain reaction assay in t(11;14)(q13;q32)-bearing B-cell malignancies and/or mantle cell lymphoma. Uchimaru, K., Taniguchi, T., Yoshikawa, M., Asano, S., Arnold, A., Fujita, T., Motokura, T. Blood (1997) [Pubmed]
  20. Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells. Sweeney, K.J., Sarcevic, B., Sutherland, R.L., Musgrove, E.A. Oncogene (1997) [Pubmed]
  21. Overexpression of cyclin D2 in chronic B-cell malignancies. Delmer, A., Ajchenbaum-Cymbalista, F., Tang, R., Ramond, S., Faussat, A.M., Marie, J.P., Zittoun, R. Blood (1995) [Pubmed]
  22. Signal transducer and activator of transcription 5 activation is sufficient to drive transcriptional induction of cyclin D2 gene and proliferation of rat pancreatic beta-cells. Friedrichsen, B.N., Richter, H.E., Hansen, J.A., Rhodes, C.J., Nielsen, J.H., Billestrup, N., Møldrup, A. Mol. Endocrinol. (2003) [Pubmed]
  23. Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Mukhopadhyay, A., Banerjee, S., Stafford, L.J., Xia, C., Liu, M., Aggarwal, B.B. Oncogene (2002) [Pubmed]
  24. Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity. Tiedemann, R.E., Mao, X., Shi, C.X., Zhu, Y.X., Palmer, S.E., Sebag, M., Marler, R., Chesi, M., Fonseca, R., Bergsagel, P.L., Schimmer, A.D., Stewart, A.K. J. Clin. Invest. (2008) [Pubmed]
  25. Follicle stimulating hormone-induced DNA synthesis in the granulosa cells of hamster preantral follicles involves activation of cyclin-dependent kinase-4 rather than cyclin d2 synthesis. Yang, P., Roy, S.K. Biol. Reprod. (2004) [Pubmed]
  26. Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes. White, P.C., Shore, A.M., Clement, M., McLaren, J., Soeiro, I., Lam, E.W., Brennan, P. Oncogene (2006) [Pubmed]
  27. Glycogen synthase kinase-3beta and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells. Kida, A., Kakihana, K., Kotani, S., Kurosu, T., Miura, O. Oncogene (2007) [Pubmed]
  28. Cell cycle regulatory proteins and apoptosis in B-cell chronic lymphocytic leukemia. Wolowiec, D., Ciszak, L., Kosmaczewska, A., Bocko, D., Teodorowska, R., Frydecka, I., Kuliczkowski, K. Haematologica (2001) [Pubmed]
  29. Mantle cell lymphoma in Taiwan: clinicopathological and molecular study of 21 cases including one cyclin D1-negative tumor expressing cyclin D2. Chuang, S.S., Huang, W.T., Hsieh, P.P., Tseng, H.H., Campo, E., Colomer, D., Ye, H., Lu, C.L., Chang, H.M., Cho, C.Y., Huang, S.H., Lu, Y.C., Wu, J.D. Pathol. Int. (2006) [Pubmed]
  30. Frequent deregulation of p16 and the p16/G1 cell cycle-regulatory pathway in neuroblastoma. Diccianni, M.B., Omura-Minamisawa, M., Batova, A., Le, T., Bridgeman, L., Yu, A.L. Int. J. Cancer (1999) [Pubmed]
  31. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Fernández de Mattos, S., Essafi, A., Soeiro, I., Pietersen, A.M., Birkenkamp, K.U., Edwards, C.S., Martino, A., Nelson, B.H., Francis, J.M., Jones, M.C., Brosens, J.J., Coffer, P.J., Lam, E.W. Mol. Cell. Biol. (2004) [Pubmed]
  32. Aberrant expression of G1-phase cell cycle regulators in flat and exophytic adenomas of the human colon. Bartkova, J., Thullberg, M., Slezak, P., Jaramillo, E., Rubio, C., Thomassen, L.H., Bartek, J. Gastroenterology (2001) [Pubmed]
  33. Up-regulation of cyclin-dependent kinase 4/cyclin D2 expression but down-regulation of cyclin-dependent kinase 2/cyclin E in testicular germ cell tumors. Schmidt, B.A., Rose, A., Steinhoff, C., Strohmeyer, T., Hartmann, M., Ackermann, R. Cancer Res. (2001) [Pubmed]
  34. Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. Takano, Y., Kato, Y., van Diest, P.J., Masuda, M., Mitomi, H., Okayasu, I. Am. J. Pathol. (2000) [Pubmed]
  35. Inactivation of cyclin D2 gene in prostate cancers by aberrant promoter methylation. Padar, A., Sathyanarayana, U.G., Suzuki, M., Maruyama, R., Hsieh, J.T., Frenkel, E.P., Minna, J.D., Gazdar, A.F. Clin. Cancer Res. (2003) [Pubmed]
  36. High-level DNA amplifications are common genetic aberrations in B-cell neoplasms. Werner, C.A., Döhner, H., Joos, S., Trümper, L.H., Baudis, M., Barth, T.F., Ott, G., Möller, P., Lichter, P., Bentz, M. Am. J. Pathol. (1997) [Pubmed]
  37. Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types. Lukas, J., Bartkova, J., Welcker, M., Petersen, O.W., Peters, G., Strauss, M., Bartek, J. Oncogene (1995) [Pubmed]
  38. Cyclin D2 interacts with cdk-5 and modulates cellular cdk-5/p35 activity. Guidato, S., McLoughlin, D.M., Grierson, A.J., Miller, C.C. J. Neurochem. (1998) [Pubmed]
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