Disease relevance of Ccnd2

• The Vin-1 gene, identified by provirus insertional mutagenesis, is the cyclin D2 [1].
• Inhibition of hypertrophy by cyclin D2 correlated with downregulation of p27Kip1 [2].

High impact information on Ccnd2

• Cyclin D2 and Ha-Ras transformed rat embryo fibroblasts exhibit a novel deregulation of cell size control and early S phase arrest in low serum [3].
• While clonal cyclin D2/Ha-Ras REF transformants exhibit a characteristic transformed phenotype in high serum, in low serum they arrest cell proliferation and display profound morphological and cytological changes indicating loss of control of cell mass and deregulation of the G1/S transition [3].
• Here, we show that cyclin D2 can co-operate with Ha-Ras to impose a novel transformed state on rat embryo fibroblasts (REF) [3].
• In addition, a drastic induction of cyclin D1 mRNA and protein, and to a lesser extent of cyclin D2 mRNA, takes place in mitogen-stimulated cells after the R point [4].
• Our results strongly support a role of the cyclin D2 gene in oncogenesis and thereby implicate altered cell cycle regulation in transformation [1].

Chemical compound and disease context of Ccnd2

• Cyclin D2 induced DNA synthesis and proliferation of cardiomyocytes and impaired hypertrophy induced by angiotensin II and serum [2].

Biological context of Ccnd2

• The sequence of the Vin-1 gene is identical to that of the recently identified G1-phase cyclin D2 gene [1].
• Sequencing of the Vin-1 cDNA and Vin-1 exons revealed that the proviruses are integrated at the 5' end of the Vin-1 gene in an inverse transcriptional orientation [1].
• The present study therefore shows that the inhibitory effect of DHT on insulin-stimulated granulosa cell proliferation occurs early in the signaling pathway at the level of insulin receptor substrate-1 phosphorylation, leading to reduced ERK phosphorylation and subsequent inhibition of cyclin D2 mRNA expression [5].
• Collectively, these data support an important functional role for cyclin D2 and cdc2 genes in determining the proliferative versus nonproliferative phenotype of AEC during lung development, injury and repair, and transformation [6].
• However, in low serum, co-operation of cyclin D2 and Ha-Ras provides only a subset of the progression signals and these are sufficient for G1-related cell mass increase and S phase entry, but are insufficient for full cell cycling [3].

Anatomical context of Ccnd2

• The Vin-1 gene was initially identified as a gene whose expression is altered by the integration of proviruses in the Vin-1 common site of integration in retrovirus-induced rodent T-cell leukemias [1].
• Forskolin treatment stimulated the expression of cyclin D2 mRNA in control granulosa cells, whereas DHT treatment abolished this response [7].
• The response to hypertrophic elicitors could be restored in differentiation inducing factor 1-treated myocytes by expressing cyclin D2 from a heterologous promoter [8].
• Differential expression of cyclin D2 and cdc2 genes in proliferating and nonproliferating alveolar epithelial cells [6].
• In contrast, high levels of cyclin D2 mRNA and protein expression were only observed in normal 19-day fetal rat AEC and in transformed mink Mv1Lu cells derived from fetal mink lung epithelium [6].

Associations of Ccnd2 with chemical compounds

• Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase [7].
• The effect of 5alpha-dihydrotestosterone (DHT) on insulin-stimulated granulosa cell proliferation was examined using cyclin D2 mRNA as a marker [5].
• Granulosa cells from 3-d estradiol-treated immature rats showed a concentration-dependent increase in cyclin D2 mRNA expression in response to insulin [5].
• Moreover, cAMP, as well as ERK and PI3K inhibitors produced equivalent stimulation and inhibition, respectively, of p27(Kip1) and cyclin D2 protein levels, potentially explaining the observation that cAMP prevented C6 cells from entering S phase [9].
• A single dose of Di-(2-ethylhexyl) phthalate in neonatal rats alters gonocytes, reduces sertoli cell proliferation, and decreases cyclin D2 expression [10].

Physical interactions of Ccnd2

• In conclusion, liver development is associated with a switch from cyclin D2/D3-containing complexes to cyclin D1:CDK4 complexes [11].

Regulatory relationships of Ccnd2

• Furthermore, blocking ERK phosphorylation as well as DHT treatment resulted in a reduction in FSH-stimulated cyclin D2 mRNA expression [12].
• The results show that the expression of rat cyclin D2 gene is not dependent on the TATA-box but is stimulated by multiple transcription factors induced by prolactin at an immediate-early stage of the cell cycle [13].

Other interactions of Ccnd2

• D-type cyclins including cyclin D1, cyclin D2, and cyclin D3 are cell cycle regulators that promote progression through the early-to-mid G1 phase of the cell cycle [14].
• Prolactin has been demonstrated to induce the expression of the genes encoding cyclin D2 and D3 during promotion of the G1/S transition in rat Nb2 pre-T-lymphoma cells. cDNA clones encoding these rat cyclins D2 and D3 were isolated and analyzed [15].
• From these results, we conclude that DHT treatment reduces the FSH-mediated ERK phosphorylation in granulosa cells, leading to reduced cyclin D2 mRNA expression that culminates in cell cycle arrest [12].
• Synergism between FSH and activin in the regulation of proliferating cell nuclear antigen (PCNA) and cyclin D2 expression in rat granulosa cells [16].
• In contrast PGF(2 alpha) inhibited the expression of two genes involved in cell cycle: cyclin D2 and retinoblastoma related protein (Rb2/p130) [17].

Analytical, diagnostic and therapeutic context of Ccnd2

• Utilizing cDNA microarray analysis, we found that mRNA level of cyclin D2 was lower in the osteoblasts from the transgenic rats [14].
• In situ hybridization and Western blot analyses demonstrated that embryonic rat brain strongly expressed cyclin D2 gene, but its expression was dramatically repressed in matured brain [18].
• We demonstrate that TCDD treatment significantly increases cyclin D2 and cyclin A protein levels and show by immunofluorescence that these proteins accumulate in the nucleus [19].
• Structure and function of the promoter region of rat cyclin D2 gene were investigated by cloning, sequence analysis and DNA mobility shift assay using nuclear extracts of prolactin-stimulated Nb2 cells [13].

References