Disease relevance of Ccnd2

• Later in life, single-cyclin mice displayed focused abnormalities, resulting in premature mortality. "Cyclin D1-only" mice developed severe megaloblastic anemia, "cyclin D2-only" mice presented neurological abnormalities, and "cyclin D3-only" mice lacked normal cerebella [1].
• Cyclin D2 overexpression in transgenic mice induces thymic and epidermal hyperplasia whereas cyclin D3 expression results only in epidermal hyperplasia [2].
• Bone marrow cells from cyclin D2-deficient strains of mice failed to proliferate in response to infection with a retrovirus carrying BCR/ABL and failed to generate transformed lymphoid cell lines in vitro [3].
• Using cellular sequences flanking a provirus cloned from one of these thymomas, we found that the viral genome was integrated into a common region, designated Vin-1, in a low percentage (5%) of these tumors [4].
• Gris1, a new common integration site in Graffi murine leukemia virus-induced leukemias: overexpression of a truncated cyclin D2 due to alternative splicing [5].

High impact information on Ccnd2

• Pitx2 then serves as a competence factor required for the temporally ordered and growth factor-dependent recruitment of a series of specific coactivator complexes that prove necessary for Cyclin D2 gene induction [6].
• To directly test the ability of each D-cyclin to drive development of various lineages, we generated mice expressing only cyclin D1, or only cyclin D2, or only cyclin D3 [1].
• Ectopic expression of cyclin D2 in rodent fibroblasts, either alone or together with exogenous cdk4, shortened their G0- to S-phase interval and reduced their serum dependency, but cyclin D2 alone did not alter cell size significantly [7].
• To address the mechanism underlying the varied proliferative responses of B-1 and B-2 cells, we evaluated the expression and activity of the G1 cell cycle regulator, cyclin D2, and its associated cyclin-dependent kinases (Cdks) [8].
• These results strongly suggest that the rapid induction of cyclin D2 by a normally nonmitogenic phorbol ester stimulus is responsible for B-1 cell progression through G1 phase [8].

Chemical compound and disease context of Ccnd2

• Treatment with the methyl transferase inhibitor 5'-aza-2'-deoxycytidine (AZAdC) increased expression of cyclin D2 and p27 in GH3 and GHRH-CL1 pituitary tumor cells [9].
• Bisulfite genomic sequencing showed that the normally unmethylated cytosines of the p27 gene in normal pituitary (NP) were extensively methylated in GH3 and GHRH-CL1 cells, but not in AtT 20, alphaT3-1 and LbetaT2 cells; but cyclin D2 was extensively inactivated in various pituitary tumor cell lines by increased DNA methylation [9].

Biological context of Ccnd2

• We describe herein that adult mice mutated in the cell cycle regulatory gene Ccnd2, encoding cyclin D2, lack newly born neurons in both of these brain structures [10].
• Cyclin D-dependent kinase activity is required for cell proliferation, yet cyclin D2(-/-) mice have normal levels of mature B-lymphocytes [11].
• Here we show that B-lymphocytes from cyclin D2(-/-) mice can proliferate in response to anti-IgM and anti-CD40, but the time taken to enter S-phase is longer than for the corresponding cyclin D2(+/+) cells [11].
• The enhanced cyclin D2 and D3 expression initiates up-regulation of cyclin E expression and down-regulation of p27(kip1) [12].
• We show that cyclin D2 induction is blocked by the PI-3K inhibitors wortmannin and LY294002, which coincides with impaired BCR-mediated mitogen-activated protein/extracellular signal-related kinase kinase (MEK)1/2 and p42/44ERK phosphorylation on activation residues [13].
• the temporal dynamics of postnatal and adult dentate gyrus neurogenesis in cyclin D2-/- mice suggests that cyclin D2 becomes essential for dentate neurogenesis at the time when the tertiary germinative matrix ceases proliferation  

Anatomical context of Ccnd2

• Furthermore, we show that cyclin D2 is the only D-type cyclin (out of D1, D2, and D3) expressed in dividing cells derived from neuronal precursors present in the adult hippocampus [10].
• This is the first demonstration that loss of a D-type cyclin causes specific expression and functional compensation by another member of the family in vivo and provides a rationale for the presence of mature B-lymphocytes in cyclin D2(-/-) mice [11].
• This model provides in vivo evidence of the action of cyclin D2 and cyclin D3 as mediators of proliferation in squamous epithelial cells [2].
• A direct comparison among the three D-type cyclin transgenic mice suggests that cyclin D1 and cyclin D2 have similar roles in epithelial thymus cells [2].
• Our results suggest a role for cyclin D2, D3, and E, and p27(kip1) proteins in the 4-1BB-mediated cell cycle progression of CD8(+) T cells in vivo [12].

Associations of Ccnd2 with chemical compounds

• These findings are further confirmed by studies showing that specific pharmacological inhibitors of Btk (LFM-A13), PI3-K (LY294002 and Wortmannin) and PLCgamma (U73122) also block cyclin D2 expression and S phase entry following BCR stimulation, as well as triggering apoptosis [14].
• Consistent with this, we also showed that the BCR-mediated cyclin D2 induction could be abolished by pretreatment of resting B cells with specific inhibitors of capacitative Ca(2+) entry (SK&F 96365) or PKC (Gö6850) [14].
• In small resting (G0) B cells, costimulation with PMA and ionomycin, but not PMA or ionomycin alone, induces cyclin D2 expression and cell-cycle progression [14].
• Cyclin D2 was translocated into the nucleus in response to E2 in the cyclin D1-/- mice to a much greater degree than in wild-type mice [15].
• However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age [16].

Physical interactions of Ccnd2

• This CDK4 activity was due to complexes of cyclin D2/CDK4 [15].
• Regulation of these two cell cycle components resulted in decreased cyclin D2/cdk2 complex and in increased p27(KIP1) association with cdk2 in C4HD cells treated with TGF-beta1 [17].

Regulatory relationships of Ccnd2

• Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression [18].
• Unexpectedly we found that this anti-mitogen raised levels of CSF-1-stimulated cyclin D2 mRNA and protein [19].
• Because cyclin D1 is a critical molecule in normal mammary lobuloalveolar development, these data suggest that overexpression of cyclin D2 may block mammary lobuloalveolar development through inhibition of cyclin D1 phosphorylation [20].
• For instance, the Ras oncogene was postulated to signal through cyclin D1, while Myc can impact the cell cycle machinery by transcriptionally upregulating cyclin D2 [21].
• Altogether our results suggest that (i) JNK1 participates in the signaling pathway which controls the expression of cyclin D2 and (ii) that the inhibition of JNK1 by DMSO and forskolin could explain, at least in part, the antiproliferative action of these drugs in 7TD1 cells [22].

Other interactions of Ccnd2

• To study the cell cycle-regulatory factors involved in ovarian, testicular, and adrenal tumor development in vivo, we have bred Inhalpha mutant mice to mice with targeted disruptions of the p27 and cyclin D2 genes [23].
• We found that double-knockout females lacking cyclin D2 and Inhalpha lived longer than mice lacking inhibins alone; the majority of these double-knockout mice lived longer than 17 wk, as opposed to inhibin alpha single-knockout females with 50% survival at between 12 and 13 wk of age [23].
• In these studies, 4-1BB costimulation was shown to increase cyclin D2, D3, and E expression, and concomitantly down-regulate the expression of the cyclin-dependent kinase inhibitor p27(kip1) [12].
• Whereas immature stage B cells increased expression of cyclin D2 and cdk4 after anti-IgM stimulation, unlike mature stage B cells they failed to express cyclin E and cdk2 [24].
• Requirement for a hsp90 chaperone-dependent MEK1/2-ERK pathway for B cell antigen receptor-induced cyclin D2 expression in mature B lymphocytes [25].
• We conclude that cyclin D3 and cyclin D2 play opposite roles in mouse skin tumor development and that the suppressive activity of cyclin D3 is associated with cyclin D2 downregulation [26].

Analytical, diagnostic and therapeutic context of Ccnd2

• Cyclin D2 levels appeared slightly enriched in germ cell-deficient testes as compared to intact testis, but in situ hybridization analysis did not reveal any distinct cellular localization [27].
• Treatment of adult rats with flutamide induced stage-dependent cyclin D2 immunoexpression in Sertoli cells within 18 h, and confocal microscopy revealed that immunoexpression of AR and cyclin D2 were mutually exclusive within individual seminiferous tubules in these animals [28].
• The levels of PCR products for cyclin D2, p27, and two forms of cdk2 were similar in meiotically incompetent and competent oocytes but decreased during oocyte maturation [29].
• Indirect immunofluorescence studies showed that cyclin D2 protein localized to the nucleus in G0, suggesting a nuclear function for cyclin D2 in quiescent cells [30].
• Transient transfection and needle microinjection of cyclin D2 expression constructs demonstrated that overexpression of cyclin D2 protein efficiently inhibited cell cycle progression and DNA synthesis [30].

References