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Gene Review

Ccnd1  -  cyclin D1

Mus musculus

Synonyms: AI327039, CycD1, Cyl-1, G1/S-specific cyclin-D1, PRAD1, ...
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Disease relevance of Ccnd1


High impact information on Ccnd1


Chemical compound and disease context of Ccnd1

  • Cyclin D1 induction is one of the earlier events in hepatocyte proliferation induced by the primary mitogen TCPOBOP and suggests that a direct effect of the mitogen on this cyclin may be responsible for the rapid onset of DNA synthesis observed in TCPOBOP-induced hyperplasia [8].
  • Adenoma growth stimulation by the trans-10, cis-12 isomer of conjugated linoleic acid (CLA) is associated with changes in mucosal NF-kappaB and cyclin D1 protein levels in the Min mouse [9].
  • Cyclin D1 content increased when lungs underwent compensatory hyperplasia following damage caused by butylated hydroxytoluene administration to mice and in lung tumor extracts as compared with extracts prepared from uninvolved tissue or control lungs [10].
  • As targets of estrogen, cyclin D1, and erbB2 signaling, these candidates offer insights into the nature of the second events involved in breast cancer progression, regulatory events contributing to invasion, and potential targets of combined inhibition of hormone and growth factor signaling pathways [11].
  • Transgenic (TG) mice with cyclin D1 overexpression targeted to the oral-esophageal tissue by the EBV ED-L2 promoter showed increased severity in esophageal dysplasia without cancer development, after multiple doses of N-nitrosomethylbenzylamine (NMBA) [12].

Biological context of Ccnd1

  • Furthermore, these mice had a 24-hour lag in the hepatic expression of the G(1)/S checkpoint regulator genes Ccnd1 and cMyc and increased expression of the IL-1beta cytokine gene [13].
  • Gene amplification occurred without overexpression since only one of five tumors with amplification and one of six tumors without Ccnd1 amplification expressed increased protein [14].
  • In turn, the ability of cyclin D-dependent kinases to trigger phosphorylation of the retinoblastoma (Rb) protein in the mid- to late G1 phase of the cell cycle makes the inactivation of Rb's growth suppressive function a mitogen-dependent step [15].
  • Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway [15].
  • Moreover, artificial elevation of cyclin D1 levels is sufficient to induce apoptosis, even in non-neural cell types [16].

Anatomical context of Ccnd1


Associations of Ccnd1 with chemical compounds

  • Inhibition of Mek1 or phosphoinositide 3-kinase markedly inhibited cyclin D1 expression and replication [21].
  • Furthermore, caffeine inhibited the activation of the cyclin D1-cdk4 complex in a dose-dependent manner [22].
  • Gefitinib concomitantly decreased cell cycle-regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis [23].
  • Proliferation-independent induction of macrophage cyclin D2, and repression of cyclin D1, by lipopolysaccharide [24].
  • Results showed that a single administration of TCPOBOP caused a very rapid increase in the levels of cyclin D1, a G1 protein, when compared with two thirds PH (8 hours versus 30 hours) [8].

Physical interactions of Ccnd1

  • Cyclin D mutants defective in binding to the retinoblastoma protein were impaired in rescuing mitogenic signaling [25].
  • In vivo proliferation of olfactory neuronal lineage cells thus involves functional binding of cyclin D1 with cdk2 and cdk4, with differential activation mechanisms for cdk2 and cdk4 [26].
  • Thus Raf mediated growth was associated with elevated p21(Cip1) expression, which may specifically bind with and activate Cdk4/cyclin D complexes and with decreased p27(Kip1) expression [27].
  • In addition, cyclin D1/cyclin-dependent kinase (CDK) complex formation increased in the transgenic mice and was correlated with elevated CDK4 and CDK6 kinase activities [28].

Enzymatic interactions of Ccnd1


Co-localisations of Ccnd1


Regulatory relationships of Ccnd1


Other interactions of Ccnd1


Analytical, diagnostic and therapeutic context of Ccnd1

  • Confocal microscopy analysis revealed cytoplasmic colocalization of cyclin D1 with SSeCKS [41].
  • ELISA and/or Northern blot analyses were done to evaluate JunB and cyclin D1 expression [35].
  • Immunoprecipitation of cdk2 and cdk4 fractions of protein extracts at 4 days postlesion (mitotic reaction peak) versus control, followed by cyclin D1 immunoblotting, and vice versa, revealed that levels of both cyclin D1/cdk2 and cyclin D1/cdk4 complexes, as well as their kinase activities, were dramatically increased after lesion [26].
  • In an effort to understand the role played by the cell cycle control in these processes, expression of cyclin D1, D2, and D3--three major positive regulators of the G1/S transition--has been investigated by in situ hybrization and RT-PCR [42].
  • While cyclin D1 expression was mainly found in the cytoplasm of the tumor cells, it shifted to the nucleus in association with cell proliferation after the animals were subjected to a partial hepatectomy (PH), and then returned once more to the cytoplasm when the cells became quiescent [43].


  1. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Rosenwald, I.B., Lazaris-Karatzas, A., Sonenberg, N., Schmidt, E.V. Mol. Cell. Biol. (1993) [Pubmed]
  2. Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice. Tong, W., Pollard, J.W. Mol. Cell. Biol. (2001) [Pubmed]
  3. Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors. Zindy, F., Uziel, T., Ayrault, O., Calabrese, C., Valentine, M., Rehg, J.E., Gilbertson, R.J., Sherr, C.J., Roussel, M.F. Cancer Res. (2007) [Pubmed]
  4. Proviral insertions near cyclin D1 in mouse lymphomas: a parallel for BCL1 translocations in human B-cell neoplasms. Lammie, G.A., Smith, R., Silver, J., Brookes, S., Dickson, C., Peters, G. Oncogene (1992) [Pubmed]
  5. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A., Fässler, R. Cell (2006) [Pubmed]
  6. Mouse development and cell proliferation in the absence of D-cyclins. Kozar, K., Ciemerych, M.A., Rebel, V.I., Shigematsu, H., Zagozdzon, A., Sicinska, E., Geng, Y., Yu, Q., Bhattacharya, S., Bronson, R.T., Akashi, K., Sicinski, P. Cell (2004) [Pubmed]
  7. IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cao, Y., Bonizzi, G., Seagroves, T.N., Greten, F.R., Johnson, R., Schmidt, E.V., Karin, M. Cell (2001) [Pubmed]
  8. Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-Bis[2-(3,5-Dichloropyridyloxy)] benzene. Ledda-Columbano, G.M., Pibiri, M., Loi, R., Perra, A., Shinozuka, H., Columbano, A. Am. J. Pathol. (2000) [Pubmed]
  9. Adenoma growth stimulation by the trans-10, cis-12 isomer of conjugated linoleic acid (CLA) is associated with changes in mucosal NF-kappaB and cyclin D1 protein levels in the Min mouse. Rajakangas, J., Basu, S., Salminen, I., Mutanen, M. J. Nutr. (2003) [Pubmed]
  10. Cyclin D1 as a proliferative marker regulating retinoblastoma phosphorylation in mouse lung epithelial cells. Mamay, C.L., Schauer, I.E., Rice, P.L., McDoniels-Silvers, A., Dwyer-Nield, L.D., You, M., Sclafani, R.A., Malkinson, A.M. Cancer Lett. (2001) [Pubmed]
  11. Identification of cyclin D1- and estrogen-regulated genes contributing to breast carcinogenesis and progression. Yang, C., Trent, S., Ionescu-Tiba, V., Lan, L., Shioda, T., Sgroi, D., Schmidt, E.V. Cancer Res. (2006) [Pubmed]
  12. Combined cyclin D1 overexpression and zinc deficiency disrupts cell cycle and accelerates mouse forestomach carcinogenesis. Fong, L.Y., Mancini, R., Nakagawa, H., Rustgi, A.K., Huebner, K. Cancer Res. (2003) [Pubmed]
  13. Delayed liver regeneration in peroxisome proliferator-activated receptor-alpha-null mice. Anderson, S.P., Yoon, L., Richard, E.B., Dunn, C.S., Cattley, R.C., Corton, J.C. Hepatology (2002) [Pubmed]
  14. A region within murine chromosome 7F4, syntenic to the human 11q13 amplicon, is frequently amplified in 4NQO-induced oral cavity tumors. Yuan, B., Oechsli, M.N., Hendler, F.J. Oncogene (1997) [Pubmed]
  15. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Diehl, J.A., Zindy, F., Sherr, C.J. Genes Dev. (1997) [Pubmed]
  16. Cyclin D1 is an essential mediator of apoptotic neuronal cell death. Kranenburg, O., van der Eb, A.J., Zantema, A. EMBO J. (1996) [Pubmed]
  17. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Toyoshima, H., Hunter, T. Cell (1994) [Pubmed]
  18. 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]
  19. ErbB2/Neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells. Muraoka, R.S., Lenferink, A.E., Law, B., Hamilton, E., Brantley, D.M., Roebuck, L.R., Arteaga, C.L. Mol. Cell. Biol. (2002) [Pubmed]
  20. A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin-dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase. Diehl, J.A., Sherr, C.J. Mol. Cell. Biol. (1997) [Pubmed]
  21. Differential regulation of cyclins D1 and D3 in hepatocyte proliferation. Rickheim, D.G., Nelsen, C.J., Fassett, J.T., Timchenko, N.A., Hansen, L.K., Albrecht, J.H. Hepatology (2002) [Pubmed]
  22. Caffeine inhibits cell proliferation by G0/G1 phase arrest in JB6 cells. Hashimoto, T., He, Z., Ma, W.Y., Schmid, P.C., Bode, A.M., Yang, C.S., Dong, Z. Cancer Res. (2004) [Pubmed]
  23. Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis. Fichera, A., Little, N., Jagadeeswaran, S., Dougherty, U., Sehdev, A., Mustafi, R., Cerda, S., Yuan, W., Khare, S., Tretiakova, M., Gong, C., Tallerico, M., Cohen, G., Joseph, L., Hart, J., Turner, J.R., Bissonnette, M. Cancer Res. (2007) [Pubmed]
  24. 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]
  25. Rescue of defective mitogenic signaling by D-type cyclins. Roussel, M.F., Theodoras, A.M., Pagano, M., Sherr, C.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  26. Unusual regulation of cyclin D1 and cyclin-dependent kinases cdk2 and cdk4 during in vivo mitotic stimulation of olfactory neuron progenitors in adult mouse. Kastner, A., Moyse, E., Bauer, S., Jourdan, F., Brun, G. J. Neurochem. (2000) [Pubmed]
  27. P21(Cip1) induced by Raf is associated with increased Cdk4 activity in hematopoietic cells. Chang, F., McCubrey, J.A. Oncogene (2001) [Pubmed]
  28. Cyclin D1 overexpression in mouse epidermis increases cyclin-dependent kinase activity and cell proliferation in vivo but does not affect skin tumor development. Rodriguez-Puebla, M.L., LaCava, M., Conti, C.J. Cell Growth Differ. (1999) [Pubmed]
  29. Role of cyclin D1 cytoplasmic sequestration in the survival of postmitotic neurons. Sumrejkanchanakij, P., Tamamori-Adachi, M., Matsunaga, Y., Eto, K., Ikeda, M.A. Oncogene (2003) [Pubmed]
  30. IkappaB kinase alpha regulates subcellular distribution and turnover of cyclin D1 by phosphorylation. Kwak, Y.T., Li, R., Becerra, C.R., Tripathy, D., Frenkel, E.P., Verma, U.N. J. Biol. Chem. (2005) [Pubmed]
  31. 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]
  32. Control of cell cycle gene expression in bone development and during c-Fos-induced osteosarcoma formation. Sunters, A., McCluskey, J., Grigoriadis, A.E. Dev. Genet. (1998) [Pubmed]
  33. Loss of Rb and Myc activation co-operate to suppress cyclin D1 and contribute to transformation. Marhin, W.W., Hei, Y.J., Chen, S., Jiang, Z., Gallie, B.L., Phillips, R.A., Penn, L.Z. Oncogene (1996) [Pubmed]
  34. Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1. Schulze, A., Zerfass, K., Spitkovsky, D., Henglein, B., Jansen-Dürr, P. Oncogene (1994) [Pubmed]
  35. PTHrP signaling targets cyclin D1 and induces osteoblastic cell growth arrest. Datta, N.S., Chen, C., Berry, J.E., McCauley, L.K. J. Bone Miner. Res. (2005) [Pubmed]
  36. Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization. Muntean, A.G., Pang, L., Poncz, M., Dowdy, S.F., Blobel, G.A., Crispino, J.D. Blood (2007) [Pubmed]
  37. Requirements for cell cycle arrest by p16INK4a. Bruce, J.L., Hurford, R.K., Classon, M., Koh, J., Dyson, N. Mol. Cell (2000) [Pubmed]
  38. Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy. Sekine, S., Gutiérrez, P.J., Lan, B.Y., Feng, S., Hebrok, M. Hepatology (2007) [Pubmed]
  39. 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]
  40. Cyclin D1 as a target for the proliferative effects of PTH and PTHrP in early osteoblastic cells. Datta, N.S., Pettway, G.J., Chen, C., Koh, A.J., McCauley, L.K. J. Bone Miner. Res. (2007) [Pubmed]
  41. SSeCKS, a major protein kinase C substrate with tumor suppressor activity, regulates G(1)-->S progression by controlling the expression and cellular compartmentalization of cyclin D. Lin, X., Nelson, P., Gelman, I.H. Mol. Cell. Biol. (2000) [Pubmed]
  42. G1-phase regulators, cyclin D1, cyclin D2, and cyclin D3: up-regulation at gastrulation and dynamic expression during neurulation. Wianny, F., Real, F.X., Mummery, C.L., Van Rooijen, M., Lahti, J., Samarut, J., Savatier, P. Dev. Dyn. (1998) [Pubmed]
  43. Neoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesis. Yamamoto, M., Tamakawa, S., Yoshie, M., Yaginuma, Y., Ogawa, K. Mol. Carcinog. (2006) [Pubmed]
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