Siah: New players in the cellular response to hypoxia

Abstract

Prolyl-hydroxylation of HIF-1α is a prerequisite for pVHL binding to HIF-1α, which results in degradation of HIF-1α by the ubiquitin-proteasome pathway. Hydroxylation of HIF-1α is mediated by the family of prolyl-hydroxylase proteins (PHD). In hypoxia, HIF-1α is stabilized as a result of inhibition of HIF-1α 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-1α to enable its association-dependent degradation by pVHL. These findings define a newly discovered layer in the regulation of HIF-1α in hypoxia. The roles of Siah activities in hypoxia responses are discussed. ©2004 Landes Bioscience.