Does inhibition of degradation of hypoxia-inducible factor (HIF) alpha always lead to activation of HIF? Lessons learnt from the effect of proteasomal inhibition on HIF activity.

At the cellular level hypoxia induces transcriptional response that is mediated by the transcription factor hypoxia-inducible factor (HIF). HIF is regulated at the level of its alpha subunit by 2-oxoglutarate (2OG)-dependent oxygenases that hydroxylate specific prolyl and asparaginyl residues of HIF-alpha, affecting its stability and activity, respectively. In the presence of O(2), the alpha subunit is degraded in a complex process with several distinct steps. In the first step, the degradation process is initiated by prolyl hydroxylases (PHDs). In the second step, the von Hippel-Lindau (VHL)/E3 ligase complex recognizes the hydroxylated HIF-alpha and mediates its polyubiquitylation by the ubiquitin-conjugating enzyme E2. In the third step, the polyubiquitylated HIF-alpha is translocated to the proteasome where it is degraded. Degradation of HIF-alpha can be inhibited at any of the three levels either by various pharmacological inhibitors or due to inactivation of genes whose products regulate the HIF system. The emerging data about inactivation of HIF under conditions of proteasomal inhibition prompted us to provide an overview contrasting the outcome of inhibition at various stages of the degradative pathway for HIF activity. Copyright 2007 Wiley-Liss, Inc.