Regulation of p53 by hypoxia: Dissociation of transcriptional repression and apoptosis from p53-dependent transactivation

Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-d ependent apoptosis in oncogenically transformed cells. Unlike DNA damage, h ypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA dama ge, hypoxia fails to induce endogenous downstream p53 effector mRNAs and pr oteins. Hypoxia does not inhibit the induction of p53 target genes by ioniz ing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the tra nscriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histo ne deacetylases that relieves transcriptional repression resulted in a sign ificant reduction of p53-dependent transrepression and hypoxia-induced apop tosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions wit h transcriptional coactivators or corepressors. Genotoxic stress induces bo th kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.