The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2

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 α transcript, p16INK4a, 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 β transcript, p14ARF, activates a p53 response manifest in elevated levels of MDM2 and p21CIP1 and cell cycle arrest in both G1 and G2/M. As a consequence, p14ARF‐induced cell cycle arrest is p53 dependent and can be abrogated by the co‐expression of human papilloma virus E6 protein. p14ARF acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14ARF expression and there is an inverse correlation between p14ARF expression and p53 function in human tumour cell lines. However, p14ARF expression is not involved in the response to DNA damage. These results place p14ARF in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.