p53-Dependent and -Independent Functions of the Arf Tumor Suppressor

Abstract

The Ink4a-Arf locus encodes two closely wedded tumor suppressor proteins (p16^Ink4a and p19^Arf) that inhibit cell proliferationby activating Rb and p53, respectively. With few exceptions, the Arf gene is repressed during mouse embryonic development,thereby helping to limit p53 expression during organogenesis. However, in adult mice, sustained hyperproliferativesignals conveyed by somatically activated oncogenes can induce Arf gene expression and trigger a p53 response that eliminatesincipient cancer cells. Disruption of this tumor surveillance pathway predisposes to cancer, and inactivation of INK4a-ARF by deletion, silencing, or mutation has been frequently observed in many forms of human cancer. Although it is acceptedthat much of Arf's tumor-suppressive activity is mediated by p53, more recent genetic evidence has pointed to additional p53-independent functions of Arf, including its ability to inhibit gene expression by a number of other transcription factors. Surprisingly,the enforced expression of Arf in mammalian cells promotes the sumoylation of several Arf-interacting proteins,implying that Arf has an associated catalytic activity. We speculate that transcriptional down-regulation in response to Arfinducedsumoylation may account for Arf's p53-independent functions.