Stress signals utilize multiple pathways to stabilize p53

The p53 tumor suppressor is activated by many diverse stress signals throug h mechanisms that result in stabilization and accumulation of the p53 prote in. p53 is normally degraded through the proteasome following interaction w ith MDM2, which both functions as a ubiquitin ligase for p53 and shuttles t o the cytoplasm, where p53 degradation occurs. Stabilization of p53 in resp onse to stress is associated with inhibition of MDM2-mediated degradation, which has been associated with phosphorylation of p53 in response to DNA da mage or activation of ARF. In this study we show distinct responses, as mea sured by phosphorylation, transcriptional activity, and subcellular localiz ation, of p53 stabilized by different activating signals. Although normal c ells and wild-type p53-expressing tumor tells showed similar responses to a ctinomycin D and camptothecin treatment, the transcriptional activity of st abilized p53 induced by deferoxamine mesylate, which mimics hypoxia, in nor mal cells was lost in all three tumor cell lines tested. Our results show t hat multiple pathways exist to stabilize p53 in response to different forms of stress, and they may involve down-regulation of MDM2 expression or regu lation of the subcellular localization of p53 or MDM2. Loss of any one of t hese pathways may predispose cells to malignant transformation, although re activation of p53 might be achieved through alternative pathways that remai n functional in these tumor cells.