THE INK4A TUMOR-SUPPRESSOR GENE-PRODUCT, P19(ARF), INTERACTS WITH MDM2 AND NEUTRALIZES MDM2S INHIBITION OF P53

The INK4a gene encodes two distinct growth inhibitors-the cyclin-depen dent kinase inhibitor p16(Ink4a), which is a component of the Rb pathw ay, and the tumor suppressor p19(Arf), which has been functionally lin ked to p53. Here we show that p19(Arf) potently suppresses oncogenic t ransformation in primary cells and that this function is abrogated whe n p53 is neutralized by viral oncoproteins and dominant-negative mutan ts but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19(Arf) and MDM2 physically interact and that p19(A rf) blocks MDM2-induced p53 degradation and transactivational silencin g, suggests that p19(Arf) functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent t umor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathway s, Rb and p53.