Abstract
Recent studies have shown that hypoxia-inducible factor1α (HIF1α) is ubiquitinated by an E3-ligase complex containing von Hippel–Lindau gene product (pVHL) after which it is targeted for proteasomal degradation. In this study, we showed that HIF1α was stabilized in the pVHL-deficient cell line 786-0 treated with a proteasome inhibitor or Co 2+. This suggests that HIF1α is also ubiquitinated by a pVHL-independent pathway and that its stability is regulated by Co 2+. Indeed, using the COS cell expression system, we confirmed that HIF1α is ubiquitinated at the N-terminal region by a pVHL-independent pathway and that its degradation is inhibited by Co 2+. We also demonstrated that Co 2+ binds to both PAS domains in the N-terminal region of HIF1α. These observations imply that the stability of HIF1α is regulated by an additional pathway through the cobalt binding of PAS domains.
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