THE ALTERNATIVE PRODUCT FROM THE HUMAN CDKN2A LOCUS, P14(ARF), PARTICIPATES IN A REGULATORY FEEDBACK LOOP WITH P53 AND MDM2

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 a transcript, p16(INK4a), is a recognized tumour suppr essor that induces a G(1) cell cycle arrest by inhibiting the phosphor ylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta tran script, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G(1) and G(2)/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 s tabilization of both p53 and MDM2. Conversely, p53 negatively regulate s 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. The se results place p14(ARF) in an independent pathway upstream of p53 an d imply that CDKN2A encodes two proteins that are involved in tumour s uppression.