Siah: new players in the cellular response to hypoxia.

Prolyl-hydroxylation of HIF-1alpha is a prerequisite for pVHL binding to HIF-1alpha, which results in degradation of HIF-1alpha by the ubiquitin-proteasome pathway. Hydroxylation of HIF-1alpha is mediated by the family of prolyl-hydroxylase proteins (PHD). In hypoxia, HIF-1alpha is stabilized as a result of inhibition of HIF-1alpha hydroxylation, which in part is achieved by decreased activity of PHD enzymes at very low oxygen concentrations. We recently demonstrated that in hypoxia the stability of 2 of 3 PHDs (1 and 3) is regulated by the E3 ligases Siah1/2. Consequently, in hypoxia Siah determines the availability of PHD1/3, which otherwise modify HIF-1alpha to enable its association-dependent degradation by pVHL. These findings define a newly discovered layer in the regulation of HIF-1alpha in hypoxia. The roles of Siah activities in hypoxia responses are discussed.