Gene and protein transfer experiments demonstrated that concurrent alterations of cyclin D1 and p16 levels cooperate to (de)regulate G1 control in diploid fibroblasts, and that both events influence growth of retinoblastoma (RB)-positive, but not RB-deficient cancer cells.
Conversely, overexpression of Wt1 attenuated the decrease in S phase induced by ORG 2058 at 48-96 h. This was accompanied by the sustained expression of cyclin D1 despite progestin treatment, and increased levels of retinoblastoma (Rb) phosphorylation at sites targeted by cyclin D1-Cdk4 (Ser249/Thr252).
Alterations of the Retinoblastoma (Rb) pathway are frequent in ovarian cancer, typically resulting from <i>CDKN2A</i> down-regulation, <i>CCNE1</i> amplification, <i>CCND1/2</i> amplification, and <i>RB1</i> loss.
We further demonstrated that ABT-263 treatment markedly increased the expression of p21<sup>Waf1/Cip1</sup> and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G<sub>1</sub>/G<sub>0</sub>-phase arrest.
Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16CDKN2 and p15CDKN2B may characterize certain cases of mantle cell NHL, and that cooperation of the abnormalities is likely to provide a growth advantage of the tumour cells through more efficient inactivation of the RB tumor suppressor.
These data suggest that inhibition of cyclin D1 expression contributes to the growth inhibition induced by the decoy oligonucleotide in MCF7 cells through a cyclin D1/Cdk4/pRB signaling pathway.
UV-C, as well as EGFR kinase inhibitors, decreased the expression level of cyclin D1 and the phosphorylated level of retinoblastoma, indicating that EGFR down-regulation is correlated to cell cycle arrest.
In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition.
We find that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner.
Two cell cycle regulators have been implicated in the pathogenesis of parathyroid neoplasms: rearrangement/overexpression of the PRAD1/cyclin D1 gene in parathyroid adenomas and inactivation of the retinoblastoma tumor suppressor gene in parathyroid carcinomas.
The protein and mRNA expressions of cyclin D1, proliferating cell nuclear antigen (PCNA), retinoblastoma (Rb), and p16 were observed with immunofluorescence and RT-PCR, respectively.
The levels of cyclin D1 and cyclin E1 and phospho-retinoblastoma, which are known to promote the cell cycle progression from G0 or G1 into S phase, were decreased in CEMIP-silenced cells.
These results suggest that the inhibitory effect of RB on cell cycle progression can be abrogated during tumor development either by loss of expression of the RB gene or by increased expression of the cyclin D1 gene.
Notably, 17/20 of our samples showed more than one alteration in the pRB pathway, however, we did not find any significant relationship between the presence of HPV, homozygous deletion of p16(INK4A) and overexpression of pRB, cyclin D1 and CDK4.
Cyclin D1 and p27<sup>Kip1</sup> regulate the activity of cyclin D1-CDK4 complexes and retinoblastoma (Rb), and then they stimulate the progression of G1/S transition and tumour cell proliferation.
Flow cytometry assay then determined that TCF over-expression helps HCC cell G1/S phase transition, and further research showed that TCF19 up-regulation inhibits p57Kip2, p21Cip1 and p27Kip1 cell cycle suppressors, enhances the expression of cyclin D1 expression and simulates retinoblastoma (Rb), FOXO1 and AKT phosphorylation.
Following further examination of cell cycle-related factors, MCM2 knockdown inhibited protein retinoblastoma (Rb), cyclin D1 and CDK4 expression, but increased p21 and p53 expression, suggesting that siMCM2 indeed triggered cell cycle arrest.In addition, siMCM2 induced apoptosis.
In vitro treatment of HCT116 cells with AS-Rb decreased the level of pRb by about 70% and also decreased the levels of the cyclin D1 protein and cyclin D1-associated kinase activity.
Nevertheless, when clustering analysis was performed, patients with tumors featuring low levels of p16, cyclin D1 and p53 with concomitantly high levels of pRB had reduced risk for relapse (Wald's p=0.015).