Opposing effects of Ras on p53: Transcriptional activation of mdm2 and induction of p19(ARF)

Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Has -driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdma induc ed by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19(A RF). This regulatory pathway accounts for the observation that cells transf ormed by oncogenic Ras are more resistant to p53-dependent apoptosis follow ing exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinas e may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19 (ARF). Levels of p53 are therefore determined by opposing effects of Raf-in duced p19(ARF) and Mdm2.