[show abstract][hide abstract] ABSTRACT: The two distinct proteins encoded by the CDKN2A locus are specified by translating the common second exon in alternative reading frames. The product of the alpha transcript, p16(INK4a), is a recognized tumour suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta transcript, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G1 and G2/M. As a consequence, p14(ARF)-induced cell cycle arrest is p53 dependent and can be abrogated by the co-expression of human papilloma virus E6 protein. p14(ARF) acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14(ARF) expression and there is an inverse correlation between p14(ARF) expression and p53 function in human tumour cell lines. However, p14(ARF) expression is not involved in the response to DNA damage. These results place p14(ARF) in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.
The EMBO Journal 10/1998; 17(17):5001-14. · 9.82 Impact Factor
[show abstract][hide abstract] ABSTRACT: The INK4a gene encodes two distinct growth inhibitors--the cyclin-dependent kinase inhibitor p16Ink4a, which is a component of the Rb pathway, and the tumor suppressor p19Arf, which has been functionally linked to p53. Here we show that p19Arf potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19Arf and MDM2 physically interact and that p19Rrf blocks MDM2-induced p53 degradation and transactivational silencing, suggests that p19Arf functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent tumor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathways, Rb and p53.
[show abstract][hide abstract] ABSTRACT: 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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