HAF: The new player in oxygen-independent HIF-1α degradation

Abstract

Adaptation to hypoxia is primarily mediated by the hypoxia-inducible transcription factor, HIF. The regulation of HIF activity by the oxygen-dependent degradation of the HIF-1α and HIF-2α subunits by the pVHL E3 ligase complex has been well characterized. We have recently described the hypoxia-associated factor, HAF, as an E3 ligase for HIF-1α that does not degrade HIF-2α. Here we summarize the mechanism of HAF-mediated HIF-1α degradation and the importance of oxygen-independent HIF-1α regulation in cancer. We also discuss the implications of the new HAF: HIF-1α degradation pathway with respect to other novel mediators of oxygen-independent HIF-α degradation. Finally, we review the significance of HAF as an isoform-specific E3 ligase in light of new information on the non-overlapping functions of HIF-1α and HIF-2α in cancer. ©2009 Landes Bioscience.