Cooperativity of p19^ARF, Mdm2, and p53 in murine tumorigenesis

Abstract

The p19^ARF gene product responds to oncogenic stresses by interfering with the inhibitory effects of Mdm2 on p53, thus enhancing p53 activity and its antiproliferative functions. The absence of p19^ARF in the mouse leads to early tumor susceptibility, presumably in part due to decreased p53 activity. To examine the tumorigenic cooperativity of p19^ARF, Mdm2, and p53 in vivo, p19^ARF-deficient mice were crossed first to p53-deficient mice and then to Mdm2 transgenic mice. The progeny were monitored for tumors. Cooperativity between p19^ARF and p53 deficiencies in accelerating tumor formation was observed for most genotypes except p53−/− p19^ARF−/− mice. p53−/− p19^ARF−/− mice had a tumor incidence similar to p53−/− mice. In this context, tumor suppression by ARF appears to be primarily p53 dependent. The majority of the p19^ARF+/− tumors deleted the wildtype p19^ARF allele, in agreement with the previous studies, suggesting that p19^ARF is a classic ‘two hit’ tumor suppressor. In a p53+/− background, however, all p19^ARF+/− tumors retained a wildtype ARF allele and most also retained wildtype p53. In the second cross between p19^ARF-deficient and Mdm2 transgenic mice, cooperativity in tumor incidence between Mdm2 overexpression and ARF deficiency was observed, consistent with the role of p19^ARF in negatively regulating Mdm2 activity. These experiments further demonstrate in vivo the inter-relationships of the p19^ARF-Mdm2-p53 signaling axis in tumor suppression.