Disease relevance of Ccnd1

• Amplification found in a number of cyclin genes, especially in cyclin D and E, is an important event process that takes place in cancers, including hepatocellular carcinoma (HCC) [1].
• Restoration of cyclin D1 expression by transfection of the cyclin D1 cDNA under transcriptional control of the cytomegalovirus promoter/enhancer in the COX-2-overexpressing (RIE-S) cells decreased the time required for S-phase entry by at least 4 h and increased the peak level of [3H]thymidine incorporation [2].
• These results show that COX-2 activity is required for cyclin D1 expression after ischemia in vivo and anoxia in vitro [3].
• Cyclooxygenase-2 activity contributes to neuronal expression of cyclin D1 after anoxia/ischemia in vitro and in vivo [3].
• Cyclin D1 mRNA expression was increased significantly in chronic hepatitis liver compared with normal liver, and then decreased in HCC and the surrounding precancerous liver of LEC rats [4].

High impact information on Ccnd1

• Recent data suggest that many tumors, such as malignant gliomas, have disrupted pRB function, either because of RB-1 gene mutations or as a result of mutations affecting upstream regulators of pRB such as cyclin D1 or p16/INK4a/MTS1 (ref. 1-5) [5].
• Activation of mitogenesis, seen in the presence of ATRA alone, was independent of extracellular signal-regulated kinase activation but correlated well with increased expression of cyclin D1 mRNA and protein [6].
• Cell death in vitro was preceded by upregulation of cyclin D1, cdk4, and increased phosphorylation of retinoblastoma protein; all are indicators of cell cycle advancement [7].
• Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death [8].
• Accordingly, we found that S-adenosylmethionine inhibits hepatocyte growth factor-induced cyclin D1 and D2 expression, activator protein 1 induction, and hepatocyte proliferation [9].

Chemical compound and disease context of Ccnd1

• Treatment with the COX-2 specific inhibitor (NS 398 25 microM) and cyclin D1 inhibitor (flavopiridol 1 microM) increased neuronal survival and inhibited DNA fragmentation after anoxia [3].
• Two weeks after uracil withdrawal, transitional cell carcinomas, with a low p27(Kip1) and high cyclin D1 and cyclin E staining pattern, could be easily distinguished from surrounding regressing epithelium [10].
• Ursodeoxycholic acid and F(6)-D(3) inhibit aberrant crypt proliferation in the rat azoxymethane model of colon cancer: roles of cyclin D1 and E-cadherin [11].
• Specific Rho kinase inhibitor, Y-27632 inhibited angiotensin II-induced cardiomyocyte hypertrophy and increased cyclin D1 [12].
• Overexpression of cyclin D1 by adenoviral gene transfer induced cardiomyocyte hypertrophy, as evidenced by increased cell size and increased protein synthesis; this hypertrophy was not diminished by concomitant treatment with fluvastatin [12].

Biological context of Ccnd1

• The ability of NO-PKG to inhibit AGE-induced cell cycle progression was verified by the observation that SNAP, SNP, and 8-pCPT-cGMP inhibited both cyclin D1 and cdk4 activation [13].
• Cyclin D1 over-expression induced hepatocytes into S phase in the absence of cell shape change on dried collagen or collagen gel [14].
• In the present study, the role of COX-2 and cyclin D1 in neuronal cell death induced by anoxia and ischemia was examined [3].
• The upregulation of cyclin D1 and follistatin mRNA at the early phase after EE administration was considered to have been affected by the upregulation of Wnt4 [15].
• Cyclin D1/CDK4-dependent kinase activity increased early during apoptosis, reaching a maximum at 9-12 h and decreasing to very low levels by 48 h [16].

Anatomical context of Ccnd1

• Regulation of the hepatocyte cell cycle by type I collagen matrix: role of cyclin D1 [14].
• Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells [17].
• We also found that ET-1 stimulation of mesangial cell proliferation was inhibited by antisense oligonucleotides directed against cyclin D1 and by overexpression of a nonphosphorylatable form of pRb [18].
• Cyclin D1 messenger RNA increased in stromal cells treated with MPA plus FGF at 9, 12, and 15 h [19].
• Cyclin D1-Cdk complexes and kinase activity correlated temporally with increased cyclin D1 expression in cells cultured with MPA plus FGF [19].

Associations of Ccnd1 with chemical compounds

• Cyclin D1 expression on collagen film was inhibited by cytochalasin D and exoenzyme C3, suggesting a role for the GTP-binding protein, Rho, in regulating cyclin D1 expression [14].
• Addition of RU 486 to cells stimulated with MPA plus FGF for 9 h reduced cyclin D1 messenger RNA accumulation by 40% [19].
• Estrogen activates cyclin-dependent kinases 4 and 6 through induction of cyclin D in rat primary osteoblasts [20].
• Flavopiridol inhibited the anoxia-induced increased expression of cyclin D1, but had no effect on COX-2 expression [3].
• NS-398 suppressed anoxia-induced expression of cyclin D1 [3].

Physical interactions of Ccnd1

• Further, during contact inhibition, there is more p21 associated with cyclin D1/Cdk4, which further contributes to the inhibition of the kinase complex [21].
• A gel shift assay demonstrated that Ets-1 binds to the ets-1 binding site of the cyclin D1 promoter in the ischemia-reperfusion condition [22].
• Cyclosporine inhibits growth through the activating transcription factor/cAMP-responsive element-binding protein binding site in the cyclin D1 promoter [23].
• We cloned and characterized the rat cyclin D1 gene 5'-flanking region and, by species- and subspecies-matched transient transfection studies, found that a basic promoter structure with a cAMP response element and two continuous Sp1-binding sites was crucial for the steady-state expression of the cyclin D1 gene [24].

Regulatory relationships of Ccnd1

• Thus, ET-1 induced cyclin D1 expression and stimulated CDK4 activity and cell cycle progression via the A-type receptor in rat mesangial cells [18].
• In exponentially growing cultures, TGF-beta 1 blocked DNA synthesis and suppressed cyclin D1 mRNA and protein expression, whereas the levels of cyclins D2, D3 and Cdk4 remained relatively unchanged [17].
• Under these conditions, CDK2 and CDK4 protein expression remained unchanged compared with proliferating cells, but expression of cyclin D1 and p27(KIP1) was down-regulated and cyclin E accumulated in the inactive form [25].
• This shape-dependent block in cell proliferation correlated with a failure to increase cyclin D1 protein level and to down-regulate the cell cycle inhibitor p27 [26].
• Cyclin D1 was up-regulated in the mid-G1 phase (4-6 h) while cyclin D3 expression emerged only in late G1 (9-12 h) [27].

Other interactions of Ccnd1

• The data suggest that the NO-PKG pathway inhibits AGE-induced proliferation by suppressing activation of JAK2-STAT5 and cyclin D1/cdk4 and induction of p21Waf1/Cip1 [13].
• Activated-Akt can activate downstream signal protein [p70(S6 K), nuclear factor (NF)-kappaB, and extracellular signal regulated kinase (ERK)], increasing the cyclin D1 level and suppressing the transcription of p27(Kip1) to enable cell cycle entry [28].
• These results indicate that cyclin D1 may be involved in the regeneration of hepatocytes rather than hepatocarcinogenesis, while Cdk4 but not Cdk6 may play an important role in the development of HCC [4].
• By contrast, significantly stronger beta-catenin and Cyclin D1 mRNA expressions and protein levels were found in CsA-treated rats than controls by RT-PCR and immunohistochemistry at week 4, whereas PCNA production was stronger at both times [29].
• CONCLUSIONS: Daily administration of low dose TA makes cell cycle open and G1 progress, possibly due to cyclin D1, CDK4 and CDK 6, their transporter p21(CIP1), and inactive p16(INK4a), which occur at quiescent hepatocytes, not stem cells [30].

Analytical, diagnostic and therapeutic context of Ccnd1

• RNase protection assay and Western immunoblotting indicated that cyclin D1 is expressed at similar levels in fetal and adult liver [31].
• When cyclin D1 was induced after partial hepatectomy, its predominant CDK-binding partner was CDK4 [31].
• The increase in cyclin D1 protein in the iron-loaded livers was paralleled by an increase in the abundance of its transcript as measured by real-time PCR [32].
• METHODS: We studied expression patterns of cyclin D1, CDK4, CDK6, p21(CIP1) and p16(INK4a) during daily intraperitoneal injection of low dose TA (50 mg/kg) till 7 day [30].
• Liver regeneration is suppressed in small-for-size liver grafts after transplantation: involvement of c-Jun N-terminal kinase, cyclin D1, and defective energy supply [33].

References