Disease relevance of CCND3

• Our data thus suggest that amplification and increased expression of CCND1 and CCND3 contribute to the loss of cell cycle control in a small fraction of human malignant gliomas [1].
• Amplification and overexpression of the CCND3 gene was detected in the glioblastoma cell line CCF-STTG1, as well as in one primary glioblastoma and in the sarcomatous component of one gliosarcoma [1].
• PURPOSE: The deregulation of CCND1, CCND2 and CCND3 genes represents a common event in multiple myeloma (MM) [2].
• This novel feature of the binding specificity of p27(kip1) to cyclins and cdk's in vivo is interpreted in the context of overexpression of cyclin D3 in the presence of high levels of p27(kip1) in human B-cell lymphomas with adverse clinical outcome [3].
• Here, we describe the regulation and role of cyclin D3 in human melanoma cells [4].

High impact information on CCND3

• Inhibition of PI3K inhibits phosphorylation of Rb, induction of cyclin D3, and degradation of p27kip1 [5].
• In thyroid tumors and cell lines, cyclin D3 expression was associated with cytoplasmic localization of p27 [6].
• Moreover, expression of cyclin D3 in thyroid carcinoma cells induced cytoplasmic retention of cotransfected p27 and rescued p27-imposed growth arrest [6].
• Cleaved Rb bound cyclin D3 and inhibited the transcriptional activity of E2F-1, but failed to bind to the regulatory protein MDM2, which has been implicated in apoptosis [7].
• Here, we show that the positive cell cycle regulator cyclin D3 [Matsushime H., Roussel M. F., Ashmun, R. A. & Sherr, C. J. (1991) Cell 65, 701-713] interacts with the death enzyme Caspase 2 [Wang, L., Miura, M., Bergeron, L., Zhu, H. & Yuan, J. (1994) Cell 78, 739-750] [8].

Chemical compound and disease context of CCND3

• Treatment of LCL with LY294002 causes a reduction of the expression of both cyclin D2 and cyclin D3, two key cyclins required for cell cycle progression but does not affect the expression of the EBV latent genes, EBNA2A or LMP-1 [9].
• The expression of cyclin D3 was studied immunohistochemically in archival formalin-fixed, paraffin-embedded specimens from normal organs obtained from three autopsy cases and 237 human primary pulmonary carcinomas [10].

Biological context of CCND3

• Cycloheximide partially blocks the induction of CCND1 and CCND3 gene expression by serum, suggesting that both de novo protein synthesis-dependent and -independent pathways contribute to induction [11].
• Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases [12].
• Assignment of the human cyclin D3 gene (CCND3) to chromosome 6p----q13 [13].
• Within cyclin D3 complexes, T-loop phosphorylation of CDK4, but not of CDK6, was directly regulated, identifying it as a determining target for cell cycle control by extracellular factors [14].
• The observations suggest that human cyclin D3 may play a fundamental role in hematopoiesis and that cyclins D1 and D2 may have different lineage- or differentiation-dependent functions [15].

Anatomical context of CCND3

• Induction of p57(Kip2) resulted in increased association of cdk6 with cyclin D3, without receptor-mediated T cell stimulation [16].
• In contrast to cyclins D1 and D2, cyclin D3 was (i) ubiquitously expressed among a panel of 70 human cultured cell types; (ii) strongly upregulated upon induction of HL-60 leukaemia cells to differentiate; and (iii) accumulated to high levels in a wide range of quiescent cell types in mouse and human differentiated tissues [17].
• In normal adult tissues, cyclin D3 showed two patterns of distribution: in lymphoid tissues it was expressed in proliferative compartments, while in most other tissues it was expressed by terminally differentiated/quiescent cells [18].
• In soft tissue neoplasms, cyclin D3 was consistently expressed in some tumours, such as stromal tumours of the gastrointestinal tract and embryonal rhabdomyosarcomas [18].
• In normal testis, the cell type-restricted expression patterns were dominated by high levels of cyclin D3 in quiescent Leydig cells and the lack of any D-type cyclin in the germ cells, the latter possibly representing the only example of normal mammalian cells proliferating in the absence of these cyclins [19].

Associations of CCND3 with chemical compounds

• 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 [20].
• In comparison, the down-regulation by curcumin of cyclin D2 and cyclin D3 was found only in selective cell lines [21].
• Differential Utilization of Cyclin D1 and Cyclin D3 in the Distinct Mitogenic Stimulations by Growth Factors and TSH of Human Thyrocytes in Primary Culture [22].
• EXPERIMENTAL DESIGN: Cyclin D3 immunoreactivity was evaluated in 223 formalin-fixed and paraffin-embedded samples of LSCC patients with a mean follow-up of 62.8 +/- 43.2 months [23].
• By Western blot analysis, we demonstrated that cyclin D3 and CDK4 protein but not other G0/G1 phase regulatory protein levels were decreased by ketoconazole-treatment in both COLO 205 and HT 29 cells [24].

Physical interactions of CCND3

• We found that cyclin D3 specifically interacted with eIF3k through its C-terminal domain [25].
• Cyclin D3 interacted with VDR in a ligand-independent manner, but treatment of the ligand, 1,25-dihydroxyvitamin D3, strengthened the interaction [26].
• Third, recombinant E2F1 binds with high affinity to the cyclin D3 promoter in vitro [27].
• These data suggest that IL-4 controls B cell proliferation by action during at least two steps of the regulation of the cell cycle, cyclin D3/cdk6 complex regulation and p27 inhibitor expression [28].
• PLC beta1 is a well-known example, given that it has been shown that only the enzyme located in the nucleus targets the cyclin D3/cdk4 complex, playing, in turn, a key role in the control of normal progression through the G1 phase of the cell cycle [29].

Co-localisations of CCND3

• Immunofluorescence experiments showed that eIF3k distributed both in nucleus and cytoplasm and colocalized with cyclin D3 [25].

Regulatory relationships of CCND3

• In cyclin D2- and D3-positive normal CD5+/CD19+ lymphocytes and B-CLL cell populations, cyclin D3 was expressed in a higher percentage of cells than cyclin D2 [30].
• Cyclin D3 is the most widely expressed D-type cyclin and can be rate limiting for G1/S transition [31].
• SARS coronavirus 7a protein blocks cell cycle progression at G0/G1 phase via the cyclin D3/pRb pathway [32].
• Cyclin D3 expression was enhanced in a cell panel of human melanoma cell lines compared with melanocytes and was regulated by fibronectin-mediated phosphatidylinositol 3-kinase/Akt signaling but not MEK activity [4].
• ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin D3 transcription in HeLa cells [33].

Other interactions of CCND3

• Interestingly, cyclin D3 and cdk4 selectively interact with phosphorylated p27(kip1) in BL40 cells [3].
• Confocal microscopy indicated that cyclin D3 overexpression was limited to areas of IE62 production, whereas cyclin B1 expression was irregular across the VZV plaque [34].
• CONCLUSION: The results provide additional insight into the mechanism of G1-S cell cycle checkpoints deregulation during stepwise pancreatic duct cell carcinogenesis, and suggest a p16-independent role for cyclin D3 in deregulating the G1 cell cycle checkpoints during early stages of pancreatic duct cell carcinogenesis [35].
• In most cases (39/46) overexpression of cyclin D3 and cyclin E was mutually exclusive possibly reflecting different underlying pathways inducing deregulated expression of these cyclins [36].
• The linearity of the RB1 pathway was clearer as only 1 of 34 DLCLs showed aberration of more than one of the components cyclin D3, p16INK4A, and pRB [37].

Analytical, diagnostic and therapeutic context of CCND3

• We postulated that evaluating CCND1 expression relative to CCND3 expression by quantitative PCR could offer an improved specificity over an evaluation of CCND1 alone [38].
• The occurrence of cyclin D3 extra signals was analyzed by fluorescence in situ hybridization in 47 randomly selected cases collected in a tissue microarray [23].
• The level of cyclin D3 at 72 h postinfection was two to three times higher than in the exponentially growing LCLs, as detected by immunoblotting [39].
• Here, we report that cyclin D3 is a new interacting partner of vitamin D receptor (VDR), a member of the superfamily of nuclear receptors for steroid hormones, thyroid hormone, and the fat-soluble vitamins A and D. The interaction was confirmed with methods of yeast two-hybrid system, in vitro binding analysis and in vivo co-immunoprecipitation [26].
• Fourth, chromatin immunoprecipitation assays demonstrate that endogenous E2F1 is associated with the cyclin D3 promoter in vivo [27].

References