Our data indicate that in spite of low or absent p16 expression, genetic alterations of the p16 and Rb tumour suppressor genes are rare in endometrial carcinogenesis.
Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines.
Retinoblastoma (Rb) tumor suppressor genes' products and of the proteins regulating its phosphorylation and function in G1 arrest, p16INK4A and cyclin D1, play important roles in the regulation of the cell cycle.
Involvement of the retinoblastoma susceptibility (RB-1), p16INK4, p53 and telomerase genes in immortalisation was examined by determining their status in 15 human cell lines representing four immortalisation complementation groups.
However, INK4 mRNA was expressed at high levels in 5 cell lines, and this was associated with deletion or inactivation of the retinoblastoma susceptibility gene product pRB but not with mutation of TP53.
DNA microarray and immunohistochemical analyses have shown that most TNBCs fall within the basal-like histological subset of breast cancers, which frequently exhibit inactivation of the retinoblastoma tumor suppressor (Rb) and upregulation of the cyclin-dependent kinase inhibitor p16(INK4a) (p16).
Although the underlying molecular-genetic pathways are not yet fully understood, the current results suggest functional reduction of the tumor suppressor genes Rb and p16 to be associated with progression of bladder cancer to a more malignant and aggressive behaviour.
The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14(ARF) and p16(INK4a), that play active roles in the p53 and Rb tumor suppressive pathways, respectively.
The Ki-67 proliferative index (Ki-67 PI) was statistically higher in the CIN group than the non-CIN group; however, there were no differences of expression of pRb and p53 between the two groups and no expression of p16INK4 in all cases.
The mammalian cell cycle is controlled by regulators of the G1 to S transition such as tumor suppressor proteins, p53 and retinoblastoma (RB); cyclin D1 and cyclin-dependent kinase 4; and inhibitor of cyclin dependent kinase, p16INK4A.
In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.<b>Experimental Design:</b> Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off).
Loss of p16INK4a expression would disrupt the retinoblastoma (Rb)/p16INK4a/cyclin D-dependent kinase (CDK4) pathway, whereas loss of p14ARF expression would inactivate both the Rb and p53/ MDM2/p14ARF pathways through MDM2, which can complex with either Rb or p53.
Several groups have recently shown that key tumour suppressors-such as members of the p53 and p16(INK4a)/retinoblastoma networks-control the efficiency of iPSC generation by activating cell-intrinsic programmes such as senescence.
The finding that ARF kills cells depending on loss of retinoblastoma activity and retention of p53 suggests that ARF may be effective in treatment of roughly 50% of head and neck cancers while sparing normal cells.
Loss of p16INK4A frees these cdks from inhibition, permitting constitutive phosphorylation of Rb and inactivation of its growth suppressive properties.
We first determined the frequency of hypermethylation of the Rb tumor suppressor gene by bisulfite sequencing and of the p16(INK4a), p14(ARF), APC, and RASSF1A tumor suppressor genes by MSP in 45 bladder cancers.