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.
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 Rb<sup>-/-</sup> p107<sup>-/-</sup> retinoblastomas, somatic copy number alterations (SCNAs) like Mdm2 amplification or Cdkn2a deletion targeting the p53-pathway occur, which is uncommon for human retinoblastoma.
We examined the expression levels of the p16, p15, p14, and retinoblastoma-susceptibility (RB) genes in primary prostate cancers and human prostate cancer cell lines, and correlated this with the DNA methylation levels of two loci in p16.
p19INK4d, a member of the INK4 family of cyclin-dependent kinase inhibitors, negatively regulates the proto-oncogenic cyclin D/CDK4(6) complexes whose ability to phosphorylate the retinoblastoma tumour suppressor (RB) promotes G1/S transition.
The tumor suppressor genes RB1 (retinoblastoma) and CDKN2a (cyclin-dependent kinase inhibitor 2a) are critical cell-cycle regulators, but their roles in human cardiomyogenesis remains unclear.
The protein products of these genes p16INK4 (p16) and pRb, respectively, like p53 protein inhibit progression from G1 to S phase. p16 exerts its function through inhibition of CDK4-mediated phosphorylation of pRb.
The expression of the retinoblastoma susceptibility (RB) gene was investigated in P19 embryonal carcinoma cells and in these cells induced to differentiate with retinoic acid (RA) or with dimethyl sulfoxide (DMSO).
In addition, genomic alterations and protein expression of the cell cycle genes CDKN2A and its alternatively spliced form, p14(ARF), as well as the retinoblastoma RB1 gene were investigated.
In familial cutaneous malignant melanoma (CMM), disruption of the retinoblastoma (pRB) pathway frequently occurs through inactivating mutations in the p16 (p16INK4A/CDKN2A/MTS1) gene or activating mutations in the G1-specific cyclin dependent kinase 4 gene (CDK4).
In addition, we report for the first time that resistance of KRAS-mutant NSCLCs to MEK inhibitor is, at least partly, due to p16 mutation status, and we described a drug combination that efficiently reactivates the RB tumor suppressor pathway to trigger radiosensitizing effects, apoptosis, and cell-cycle arrest.
Cells within certain neurofibroma subtypes subsequently accumulate additional mutations affecting the p19(ARF)-MDM2-TP53 and p16INK4A-Rb signaling cascades, mutations of other as yet unidentified genes, and amplification of growth factor receptor genes, resulting in their transformation into MPNSTs.
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.
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.
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.
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).