HGNC Approved Gene Symbol: CCND3
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:41,934,933-42,050,035 (from NCBI)
Using murine cDNA clones for 3 cyclin D genes that are normally expressed during the G1 phase of the cell cycle, Inaba et al. (1992) cloned the cognate human genes. Motokura et al. (1992) also cloned the CCND3 gene. Xiong et al. (1992) cloned CCND3 and found that all 3 human D-type cyclin genes encode small (33-34 kD) proteins that share an average of 57% identity over the entire coding region and 78% in the cyclin box. The D-type cyclins are most closely related to cyclin A (39% identity) and cyclin E (36%), followed by cyclin B (29%) and cyclin C (21%).
Motokura et al. (1992) found that in normal human mammary epithelial cells synchronized by growth factor deprivation and subsequent growth factor stimulation, PRAD1/cyclin D1 (CCND1; 168461) expression peaked in G1 and declined before the S phase, while cyclin D3 expression rose later in G1 and remained elevated in S.
By yeast 2-hybrid analysis, Shen et al. (2004) identified EIF3S12 (609596) as a binding partner of cyclin D3. The interaction was mediated by the C terminus of cyclin D3. GST pull-down experiments and transient transfections showed that EIF3S12 and cyclin D3 bound both in vitro and in vivo, and EIF3S12 did not bind cyclin D1 or D2 (CCND2; 123833). Immunofluorescence revealed EIF3S12 distributed in the nucleus and cytoplasm in a pattern that overlapped with that of cyclin D3. In addition, overexpression of cyclin D3 upregulated the translational activity in HeLa cells in a dose-dependent manner.
Using human cancer cells and patient-derived xenografts in mice, Wang et al. (2017) showed that the cyclin D3-CDK6 (603368) kinase phosphorylates and inhibits the catalytic activity of 2 key enzymes in the glycolytic pathway, 6-phosphofructokinase (PFK1; see PFKP, 171840) and pyruvate kinase M2 (PKM2; see 179050). This redirects the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduced flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increased the levels of reactive oxygen species and caused apoptosis of tumor cells. The prosurvival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. Wang et al. (2017) proposed that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon inhibition of CDK4 and CDK6.
Inaba et al. (1992) determined that all 3 cyclin D genes are interrupted by an intron at the same position.
Wang et al. (1996) showed that the mouse cyclin D3 gene contains 5 exons spanning about 7 kb of genomic DNA. They confirmed the activity of the gene promoter by linking the CCND3 1,681-bp 5-prime region to a reporter gene and transiently transfecting various cell lines. Greatest expression of the reporter gene was detected in cell lines that normally expressed high levels of endogenous cyclin D3 mRNA.
By analysis of somatic cell hybrids containing different human chromosomes and by fluorescence in situ hybridization to metaphase spreads from normal peripheral blood lymphocytes, Inaba et al. (1992) assigned the CCND3 gene to 6p21. Motokura et al. (1992) mapped the gene to chromosome 6 by use of human/rodent hybrids. Xiong et al. (1992) mapped the CCND3 gene to 6p21 by fluorescence in situ hybridization.
Xiong et al. (1992) identified a pseudogene corresponding to CCND2 and one corresponding to CCND3 (123834). Inaba et al. (1992) found that pseudogenes containing sequences related to cyclin D2 and cyclin D3 map to 12p13 and 6p21, respectively.
Kozar et al. (2004) tested the requirement for D-cyclins in mouse development and in proliferation by generating mice lacking all D-cyclins. Ccnd1 -/- Ccnd2 -/- Ccnd3 -/- mice developed until mid/late gestation and died due to heart abnormalities combined with severe anemia. The authors found that D-cyclins were critically required for expansion of hematopoietic stem cells. In contrast, cyclin D-deficient fibroblasts proliferated nearly normally, but showed increased requirement for mitogenic stimulation in cell cycle reentry. Proliferation of Ccnd1 -/- Ccnd2 -/- Ccnd3 -/- cells was resistant to inhibition by p16(INK4a) (600160), but it critically depended on CDK2 (116953). Cells lacking D-cyclins displayed reduced susceptibility to oncogenic transformation.
Inaba, T., Matsushime, H., Valentine, M., Roussel, M. F., Sherr, C. J., Look, A. T. Genomic organization, chromosomal localization, and independent expression of human cyclin D genes. Genomics 13: 565-574, 1992. [PubMed: 1386335] [Full Text: https://doi.org/10.1016/0888-7543(92)90126-d]
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. Mouse development and cell proliferation in the absence of D-cyclins. Cell 118: 477-491, 2004. [PubMed: 15315760] [Full Text: https://doi.org/10.1016/j.cell.2004.07.025]
Motokura, T., Keyomarsi, K., Kronenberg, H. M., 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: 20412-20415, 1992. [PubMed: 1383201]
Motokura, T., Yi, H. F., Kronenberg, H. M., McBride, O. W., Arnold, A. Assignment of the human cyclin D3 gene (CCND3) to chromosome 6p-q13. Cytogenet. Cell Genet. 61: 5-7, 1992. [PubMed: 1387066] [Full Text: https://doi.org/10.1159/000133359]
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: 139-146, 2004. [PubMed: 15327989] [Full Text: https://doi.org/10.1016/j.febslet.2004.07.071]
Wang, H., Nicolay, B. N., Chick, J. M., Gao, X., Geng, Y., Ren, H., Gao, H., Yang, G., Williams, J. A., Suski, J. M., Keibler, M. A., Sicinska, E., Gerdemann, U., Haining, W. N., Roberts, T. M., Polyak, K., Gygi, S. P., Dyson, N. J., Sicinski, P. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546: 426-430, 2017. [PubMed: 28607489] [Full Text: https://doi.org/10.1038/nature22797]
Wang, Z., Sicinski, P., Weinberg, R. A., Zhang, Y., Ravid, K. Characterization of the mouse cyclin D3 gene: exon/intron organization and promoter activity. Genomics 35: 156-163, 1996. [PubMed: 8661116] [Full Text: https://doi.org/10.1006/geno.1996.0334]
Xiong, Y., Menninger, J., Beach, D., Ward, D. C. Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins. Genomics 13: 575-584, 1992. [PubMed: 1386336] [Full Text: https://doi.org/10.1016/0888-7543(92)90127-e]