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Gene Review

CCND1  -  cyclin D1

Homo sapiens

Synonyms: B-cell lymphoma 1 protein, BCL-1, BCL-1 oncogene, BCL1, D11S287E, ...
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Disease relevance of CCND1

  • We report here that CCND1 promoter activation by estrogens in human breast cancer cells is mediated by recruitment of a c-Jun/c-Fos/estrogen receptor alpha complex to the tetradecanoyl phorbol acetate-responsive element of the gene, together with Oct-1 to a site immediately adjacent [1].
  • Rearrangement of CCND1 (BCL1/PRAD1) 3' untranslated region in mantle-cell lymphomas and t(11q13)-associated leukemias [2].
  • Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types [3].
  • To define further the prevalence of such rearrangements, we report here the result of the molecular study of 34 MCL and six t(11q13)-associated leukemias using a set of probes specific to the different parts of the CCND1 transcript [2].
  • CCND1 amplifications were associated with the pharyngeal site in primary carcinomas (P < 0.001), whereas amplifications of ZNF217 were less frequent in pharyngeal carcinomas as compared with primary oral and laryngeal carcinomas (P = 0.02) [4].
  • Cyclin D1 overexpression is associated with longer survival in colon cancer [5].

Psychiatry related information on CCND1

  • Our data indicated an association with alcohol consumption and the CCND1 gene or protein levels, in both esophageal and gastric cancers [6].
  • These results suggest that the expression level of cyclin D1 RNA in bone marrow cells is predictive of the phase evolution in CML and may be helpful in treatment decision-making [7].
  • Using a spontaneous transplantable murine model of B cell leukemia/lymphoma (BCL1), we have demonstrated the expression of the B7 costimulatory molecules in addition to the previously described Id determinant and class II major histocompatibility antigens [8].

High impact information on CCND1

  • The PRAD1 gene of parathyroid adenomas appears to be the elusive Bcl-1 gene of t(11;14)(q13;q32) bearing lymphomas [9].
  • A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer [10].
  • Notably, either inhibiting apoptosis (by exogenously expressing antiapoptotic Bcl family proteins) or enhancing proliferation (via Cyclin D1 or HPV E7 overexpression) does not result in luminal filling, suggesting glandular architecture is resistant to such isolated oncogenic insults [11].
  • Interference with cyclin D1 degradation prevents initiation of G1 arrest and renders cells more susceptible to DNA damage, indicating that cyclin D1 degradation is an essential component of the cellular response to genotoxic stress [12].
  • Dominant-negative PIKE prevents the NGF enhancement of PI3K and upregulation of cyclin D1 [13].

Chemical compound and disease context of CCND1


Biological context of CCND1


Anatomical context of CCND1

  • Moreover, the finding that the CCND1 mRNA half-life was greater than 3 hours (normal tissues, 0.5 hours) in three t(11q13)-associated cell lines stresses the importance of posttranscriptional derangement in the activation of CCND1 [2].
  • Appropriate CCND1 gene activity is essential for normal development and physiology of the mammary gland, where it is regulated by ovarian steroids through a mechanism(s) that is not fully elucidated [1].
  • CCND1 GG was associated with G3 tumors in the oral cavity/pharyngeal (P = 0.011), but not laryngeal, SCC cases [23].
  • FISH analysis revealed that cyclin D1 over-expression was caused by t(11;14)(q13;q32) or extra copies of B-cell leukemia/lymphoma-1 (BCL-1/CCND1), and unknown mechanism without them [24].
  • These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis [25].

Associations of CCND1 with chemical compounds

  • Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors [14].
  • The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 muM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells [26].
  • A common adenine-to-guanine substitution polymorphism (A870G) in the CCND1 gene results in an altered messenger RNA transcript and a longer-life protein, which are preferentially encoded by the A allele [27].
  • We show here a novel role for cyclin D1 in growth regulation of estrogen-responsive tissues by potentiating transcription of estrogen receptor-regulated genes [28].
  • Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1 [29].
  • This degradation is independent of phosphorylation of cyclin D1 at threonine 286, which is mediated by the glycogen synthase kinase 3beta and mitogen-activated protein kinase pathways as described in previous studies [30].

Physical interactions of CCND1

  • Both in vivo and in vitro, the abundance of assembled cdk4/cyclin D complex increases directly with increasing inhibitor levels [31].
  • In contrast, amino-terminal sequences were identified, including the PSTAIRE region, that are important for cyclin D1 binding but are not involved in p16 binding [32].
  • A proposed mechanism is p21 sequestration into cyclin D1.Cdk4/6 complexes driven by estrogen-induced transcriptional activation of cyclin D1 gene expression [33].
  • Deletion of the N-terminal cyclin D1 binding site severely compromised AR activity (due to loss of FxxLF) but unmasked a repressor action through interaction with the AR C terminus [34].
  • Using immunoprecipitation with the anti-cyclin D anti-body, cyclin D can be found in a complex with Cdc2 in suspension-cultured tobacco BY-2 cells [35].

Enzymatic interactions of CCND1

  • Expression of wild-type PTEN but not of mutant forms unable to dephosphorylate phosphoinositides reduced the expression of cyclin D1 [36].
  • Transduction of BT-474 cells with an adenovirus-encoding active (myristoylated) Akt (Myr-Akt), but not with a beta-galactosidase control adenovirus, prevented the Herceptin- or LY294002-induced down-regulation of cyclin D1 and of phosphorylated GSK-3beta and prevented the accumulation of p27 in the nucleus and cytosol [37].
  • Under these same conditions, phosphorylated c-Myc was rapidly down-regulated (by 4 h), while the levels of cyclin D1 and phosphorylated p38 were constant [38].

Regulatory relationships of CCND1


Other interactions of CCND1


Analytical, diagnostic and therapeutic context of CCND1


  1. Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. Cicatiello, L., Addeo, R., Sasso, A., Altucci, L., Petrizzi, V.B., Borgo, R., Cancemi, M., Caporali, S., Caristi, S., Scafoglio, C., Teti, D., Bresciani, F., Perillo, B., Weisz, A. Mol. Cell. Biol. (2004) [Pubmed]
  2. Rearrangement of CCND1 (BCL1/PRAD1) 3' untranslated region in mantle-cell lymphomas and t(11q13)-associated leukemias. Rimokh, R., Berger, F., Bastard, C., Klein, B., French, M., Archimbaud, E., Rouault, J.P., Santa Lucia, B., Duret, L., Vuillaume, M. Blood (1994) [Pubmed]
  3. Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. Korz, C., Pscherer, A., Benner, A., Mertens, D., Schaffner, C., Leupolt, E., Döhner, H., Stilgenbauer, S., Lichter, P. Blood (2002) [Pubmed]
  4. Tissue microarray analysis reveals site-specific prevalence of oncogene amplifications in head and neck squamous cell carcinoma. Freier, K., Joos, S., Flechtenmacher, C., Devens, F., Benner, A., Bosch, F.X., Lichter, P., Hofele, C. Cancer Res. (2003) [Pubmed]
  5. A cohort study of cyclin D1 expression and prognosis in 602 colon cancer cases. Ogino, S., Nosho, K., Irahara, N., Kure, S., Shima, K., Baba, Y., Toyoda, S., Chen, L., Giovannucci, E.L., Meyerhardt, J.A., Fuchs, C.S. Clin. Cancer Res. (2009) [Pubmed]
  6. Alterations of the CCND1 and HER-2/neu (ERBB2) proteins in esophageal and gastric cancers. Bizari, L., Borim, A.A., Leite, K.R., Gonçalves, F.d.e. .T., Cury, P.M., Tajara, E.H., Silva, A.E. Cancer Genet. Cytogenet. (2006) [Pubmed]
  7. Overexpression of cyclin D1 in accelerated-phase chronic myeloid leukemia. Liu, J.H., Yen, C.C., Lin, Y.C., Gau, J.P., Yang, M.H., Chao, T.C., Hsiao, L.T., Wang, W.S., Tsai, Y.C., Chen, P.M. Leuk. Lymphoma (2004) [Pubmed]
  8. Induction of tumor immunity by intact irradiated leukemic B cells (BCL1) bearing a tumor-associated cell-surface idiotype and the costimulatory B7 molecule. Morecki, S., Levi, S., Puyesky, Y., Slavin, S. Cancer Immunol. Immunother. (1995) [Pubmed]
  9. Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. Korsmeyer, S.J. Annu. Rev. Immunol. (1992) [Pubmed]
  10. A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Lamb, J., Ramaswamy, S., Ford, H.L., Contreras, B., Martinez, R.V., Kittrell, F.S., Zahnow, C.A., Patterson, N., Golub, T.R., Ewen, M.E. Cell (2003) [Pubmed]
  11. The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Debnath, J., Mills, K.R., Collins, N.L., Reginato, M.J., Muthuswamy, S.K., Brugge, J.S. Cell (2002) [Pubmed]
  12. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Agami, R., Bernards, R. Cell (2000) [Pubmed]
  13. Pike. A nuclear gtpase that enhances PI3kinase activity and is regulated by protein 4.1N. Ye, K., Hurt, K.J., Wu, F.Y., Fang, M., Luo, H.R., Hong, J.J., Blackshaw, S., Ferris, C.D., Snyder, S.H. Cell (2000) [Pubmed]
  14. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Jirström, K., Stendahl, M., Rydén, L., Kronblad, A., Bendahl, P.O., Stål, O., Landberg, G. Cancer Res. (2005) [Pubmed]
  15. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Moreno-Bueno, G., Rodríguez-Perales, S., Sánchez-Estévez, C., Hardisson, D., Sarrió, D., Prat, J., Cigudosa, J.C., Matias-Guiu, X., Palacios, J. Oncogene (2003) [Pubmed]
  16. Association of cyclin D1 genotype with breast cancer risk and survival. Shu, X.O., Moore, D.B., Cai, Q., Cheng, J., Wen, W., Pierce, L., Cai, H., Gao, Y.T., Zheng, W. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  17. Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma. Schernhammer, E.S., Tranah, G.J., Giovannucci, E., Chan, A.T., Ma, J., Colditz, G.A., Hunter, D.J., Willett, W.C., Fuchs, C.S. Br. J. Cancer (2006) [Pubmed]
  18. Cyclin D1 overexpression in invasive breast cancers: correlation with cyclin-dependent kinase 4 and oestrogen receptor overexpression, and lack of correlation with mitotic activity. Takano, Y., Takenaka, H., Kato, Y., Masuda, M., Mikami, T., Saegusa, M., Okayasu, I. J. Cancer Res. Clin. Oncol. (1999) [Pubmed]
  19. Growth-regulated expression of D-type cyclin genes in human diploid fibroblasts. Won, K.A., Xiong, Y., Beach, D., Gilman, M.Z. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  20. 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]
  21. Chromosomal rearrangements and oncogene amplification precede aneuploidization in the genetic evolution of breast cancer. Rennstam, K., Baldetorp, B., Kytölä, S., Tanner, M., Isola, J. Cancer Res. (2001) [Pubmed]
  22. Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Zatyka, M., da Silva, N.F., Clifford, S.C., Morris, M.R., Wiesener, M.S., Eckardt, K.U., Houlston, R.S., Richards, F.M., Latif, F., Maher, E.R. Cancer Res. (2002) [Pubmed]
  23. Cyclin D1, glutathione S-transferase, and cytochrome P450 genotypes and outcome in patients with upper aerodigestive tract cancers: assessment of the importance of individual genes using multivariate analysis. Matthias, C., Jahnke, V., Jones, P.W., Hoban, P.R., Alldersea, J.E., Worrall, S.F., Fryer, A.A., Strange, R.C. Cancer Epidemiol. Biomarkers Prev. (1999) [Pubmed]
  24. Cyclin D1 overexpression is not a specific grouping marker, but may collaborate with CDC37 in myeloma cells. Katayama, Y., Sakai, A., Okikawa, Y., Oue, N., Asaoku, H., Sasaki, A., Imanaka, F., Tsujimoto, T., Takimoto, Y., Masuda, R., Nakaju, N., Otsuki, T., Yasui, W., Kimura, A. Int. J. Oncol. (2004) [Pubmed]
  25. Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction. Bièche, I., Franc, B., Vidaud, D., Vidaud, M., Lidereau, R. Thyroid (2001) [Pubmed]
  26. Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line. Zhang, P., Zhang, Z., Zhou, X., Qiu, W., Chen, F., Chen, W. BMC Cancer (2006) [Pubmed]
  27. Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer. Le Marchand, L., Seifried, A., Lum-Jones, A., Donlon, T., Wilkens, L.R. JAMA (2003) [Pubmed]
  28. CDK-independent activation of estrogen receptor by cyclin D1. Zwijsen, R.M., Wientjens, E., Klompmaker, R., van der Sman, J., Bernards, R., Michalides, R.J. Cell (1997) [Pubmed]
  29. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Zwijsen, R.M., Buckle, R.S., Hijmans, E.M., Loomans, C.J., Bernards, R. Genes Dev. (1998) [Pubmed]
  30. PKR and PKR-like endoplasmic reticulum kinase induce the proteasome-dependent degradation of cyclin D1 via a mechanism requiring eukaryotic initiation factor 2alpha phosphorylation. Raven, J.F., Baltzis, D., Wang, S., Mounir, Z., Papadakis, A.I., Gao, H.Q., Koromilas, A.E. J. Biol. Chem. (2008) [Pubmed]
  31. New functional activities for the p21 family of CDK inhibitors. LaBaer, J., Garrett, M.D., Stevenson, L.F., Slingerland, J.M., Sandhu, C., Chou, H.S., Fattaey, A., Harlow, E. Genes Dev. (1997) [Pubmed]
  32. Identification of CDK4 sequences involved in cyclin D1 and p16 binding. Coleman, K.G., Wautlet, B.S., Morrissey, D., Mulheron, J., Sedman, S.A., Brinkley, P., Price, S., Webster, K.R. J. Biol. Chem. (1997) [Pubmed]
  33. A low abundance pool of nascent p21WAF1/Cip1 is targeted by estrogen to activate cyclin E*Cdk2. Prall, O.W., Carroll, J.S., Sutherland, R.L. J. Biol. Chem. (2001) [Pubmed]
  34. Cyclin D1 binding to the androgen receptor (AR) NH2-terminal domain inhibits activation function 2 association and reveals dual roles for AR corepression. Burd, C.J., Petre, C.E., Moghadam, H., Wilson, E.M., Knudsen, K.E. Mol. Endocrinol. (2005) [Pubmed]
  35. Tobacco retinoblastoma-related protein phosphorylated by a distinct cyclin-dependent kinase complex with Cdc2/cyclin D in vitro. Nakagami, H., Sekine, M., Murakami, H., Shinmyo, A. Plant J. (1999) [Pubmed]
  36. PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Radu, A., Neubauer, V., Akagi, T., Hanafusa, H., Georgescu, M.M. Mol. Cell. Biol. (2003) [Pubmed]
  37. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Yakes, F.M., Chinratanalab, W., Ritter, C.A., King, W., Seelig, S., Arteaga, C.L. Cancer Res. (2002) [Pubmed]
  38. Protein expression of PDZ-binding kinase is up-regulated in hematologic malignancies and strongly down-regulated during terminal differentiation of HL-60 leukemic cells. Nandi, A., Tidwell, M., Karp, J., Rapoport, A.P. Blood Cells Mol. Dis. (2004) [Pubmed]
  39. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Tetsu, O., McCormick, F. Nature (1999) [Pubmed]
  40. Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle. Mettouchi, A., Klein, S., Guo, W., Lopez-Lago, M., Lemichez, E., Westwick, J.K., Giancotti, F.G. Mol. Cell (2001) [Pubmed]
  41. Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Khleif, S.N., DeGregori, J., Yee, C.L., Otterson, G.A., Kaye, F.J., Nevins, J.R., Howley, P.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  42. Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells. Lim, J.T., Mansukhani, M., Weinstein, I.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  43. 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]
  44. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Serrano, M., Hannon, G.J., Beach, D. Nature (1993) [Pubmed]
  45. Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Pagano, M., Theodoras, A.M., Tam, S.W., Draetta, G.F. Genes Dev. (1994) [Pubmed]
  46. A novel mechanism by which thiazolidinediones facilitate the proteasomal degradation of cyclin D1 in cancer cells. Wei, S., Yang, H.C., Chuang, H.C., Yang, J., Kulp, S.K., Lu, P.J., Lai, M.D., Chen, C.S. J. Biol. Chem. (2008) [Pubmed]
  47. Polymorphism of the cyclin D1 gene, CCND1, and risk for incident sporadic colorectal adenomas. Lewis, R.C., Bostick, R.M., Xie, D., Deng, Z., Wargovich, M.J., Fina, M.F., Roufail, W.M., Geisinger, K.R. Cancer Res. (2003) [Pubmed]
  48. 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]
  49. TP53 gene mutations and CCND1 gene amplification in head and neck squamous cell carcinoma cell lines. Xu, L., Davidson, B.J., Murty, V.V., Li, R.G., Sacks, P.G., Garin-Chesa, P., Schantz, S.P., Chaganti, R.S. Int. J. Cancer (1994) [Pubmed]
  50. Rearrangements and increased expression of cyclin D1 (CCND1) in neuroblastoma. Molenaar, J.J., van Sluis, P., Boon, K., Versteeg, R., Caron, H.N. Genes Chromosomes Cancer (2003) [Pubmed]
  51. External imaging of CCND1 cancer gene activity in experimental human breast cancer xenografts with 99mTc-peptide-peptide nucleic acid-peptide chimeras. Tian, X., Aruva, M.R., Qin, W., Zhu, W., Duffy, K.T., Sauter, E.R., Thakur, M.L., Wickstrom, E. J. Nucl. Med. (2004) [Pubmed]
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