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Hypoxia-inducible factor-1 (HIF-1) controls the expression of a number of genes such as vascular endothelial growth factor and erythropoietin in low oxygen conditions. However, the molecular mechanisms that underlie the activation of the limiting subunit, HIF-1α, are still poorly resolved. Results showing that endogenous HIF-1α migrated 12 kDa higher than in vitrotranslated protein led us to evaluate the possible role of phosphorylation on this phenomenon. We report here that HIF-1α is strongly phosphorylated in vivo and that phosphorylation is responsible for the marked differences in the migration pattern of HIF-1α. In vitro, HIF-1α is phosphorylated by p42 and p44 mitogen-activated protein kinases (MAPKs) and not by p38 MAPK or c-Jun N-terminal kinase. Interestingly, p42/p44 MAPK stoichiometrically phosphorylate HIF-1α in vitro, as judged by a complete upper shift of HIF-1α. More importantly, we …