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.
Nakayama
Koh
K
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Ronai
Ze'ev
Z
D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D011506:Proteins; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C484442:Siah1a protein, mouse; D044767:Ubiquitin-Protein Ligases