Direct interactions between HIF-1α and Mdm2 modulate p53 function

The p53 tumor suppressor is maintained at low levels in normal cells by Mdm2-mediated degradation and strongly stabilized in response to various types of stress including hypoxia. Although hypoxia-inducible factor 1alpha (HIF-1alpha) has been implicated to be involved in p53 stabilization, the precise mechanism by which HIF-1alpha regulates p53-mediated function remains unknown. Here, we found that HIF-1alpha directly binds Mdm2 both in vitro and in vivo; in contrast, p53 fails to directly interact with HIF-1alpha in vitro. Interestingly, Mdm2 expression can significantly enhance the in vivo association between p53 and HIF-1alpha, indicating that Mdm2 may act as a bridge and mediate the indirect interaction between HIF-1alpha and p53 in cells. Furthermore, HIF-1alpha protects p53 degradation mediated by Mdm2, and leads to activation of p53-mediated transcription in cells. To elucidate the mechanism of HIF-1alpha-mediated effect, we also found that HIF-1alpha can significantly suppress Mdm2-mediated p53 ubiquitination in vitro and blocks Mdm2-mediated nuclear export of p53. These results have significant implications regarding the molecular mechanism by which p58 is activated by HIF-1alpha in response to hypoxia.