Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers. We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.
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PMID:Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. 991 6

The signal transduction pathway regulated by the retinoblastoma tumor suppressor protein, pRB, is abrogated in the majority of human cancers. Using a series of cell lines derived from oral squamous cell carcinomas (SCCs) that were not subjected to radiation or chemotherapy treatment, we detected specific hyperactivity of cyclin dependent kinase (cdk) 6 but not cdk4. Subcellular localization studies showed a predominant nuclear localization of cdk6, demonstrating that this kinase was biologically active. The molecular basis for this aberration are mutations in the MTS1 locus of chromosome 9p21. This locus encodes two partially overlapping genes, the cdk inhibitor p16(ink4a), and p14(ARF), an inhibitor of mdm2-mediated degradation of p53. Our analysis demonstrates that the mutations of the MTS1 locus in oral SCC specifically target expression of the p16(ink4a) gene but less frequently affect p14(ARF). These results suggest that hyperactivity of cdk6 represents a distinct mechanism for pRB inactivation in oral SCC.
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PMID:Aberrations in the MTS1 tumor suppressor locus in oral squamous cell carcinoma lines preferentially affect the INK4A gene and result in increased cdk6 activity. 1185 66

Based on the concept that tumor suppressor genes are involved in the pathogenesis of urinary bladder carcinogenesis, we analysed the mRNA expression of the retinoblastoma (Rb) and p16 (CDKN2, INK4A, MTS1) genes as well as of the proto-oncogene cyclin D-dependent kinase 4 (CDK4) in 71 transitional cell carcinomas (TCC) of the urinary bladder in relation to the tumor grades and stages, and with reference to certain lifestyle and occupational risk factors. Using real-time quantitative reverse transcription-polymerase chain reaction, high-stage muscle invasive TCC expressed the Rb, p16 and CDK4 mRNA at lower levels than low-stage superficial cancers, indicating down-regulation to be linked with tumor progression. The drop of the expression in the group of grade 2 TCC when invading the muscle layer compared to grade 2 carcinomas with a superficial pattern of growth is considered to represent a key event in promoting urothelial carcinogenesis in this subset of carcinomas. The protein expression of the Rb gene evaluated by immunohistochemistry proved to be closely related to the tumor grades and stages as well as to the mRNA expression, high-grade and high-stage TCC disclosing a lower rate of positive immunoreactivity than low-grade and low-stage carcinomas. The p16 protein product was expressed at a lower level in grade 3 than in grade 1 TCC, but there was no correlation with the tumor stages or the mRNA expression. TCC with loss of heterozygosity (LOH) at the INK4A region showed a decreased expression of p16 mRNA compared to those without an allelic loss. Tobacco smoke was not identified to substantially modulate the Rb/p16/CDK4 pathways, except for a ten-fold elevated mRNA expression of the p16 gene in TCC of light compared to heavy smokers. Heavy coffee consumption was associated with a reduced expression of CDK4 mRNA. Among occupational exposures, TCC of patients in contact with stone dust, paints and lacquer, plastics, wood and wood preservers and chemical solvents and adhesives displayed altered partly elevated, partly reduced levels of Rb, p16 and CDK4 mRNA compared to non-exposed subjects. 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.
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PMID:Altered mRNA expression of the Rb and p16 tumor suppressor genes and of CDK4 in transitional cell carcinomas of the urinary bladder associated with tumor progression. 1516 Oct 57


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