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Dynamic, Site-specific Interaction of Hypoxia-inducible Factor-1 with the von Hippel-Lindau Tumor Suppressor Protein¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Hypoxia-inducible factor (HIF)-1 is a transcription factor that plays a critical role in regulating genes involved in erythropoiesis and angiogenesis. Recent evidence indicates that the von Hippel-Lindau tumor suppressor protein (VHL) is part of a ubiquitin ligase complex that promotes the degradation of HIF-1 under normoxic conditions. Under hypoxic conditions, HIF-1 is markedly stabilized. A critical issue in understanding the hypoxic response is the identification of hypoxia-regulated steps. We show here that hypoxia and cobalt treatment modulate the capacity of a HIF-1 fragment comprising residues 531–652 to coimmunoprecipitate with VHL. Hypoxia and cobalt both significantly diminish the interaction, and furthermore, normoxia treatment after hypoxia rapidly normalizes it. This HIF-1 fragment confers hypoxia and cobalt inducibility on a heterologous protein. Significantly, contained within this fragment is a short 27-residue sequence that behaves identically in all respects noted above. Finally, evidence is provided to show that cobalt and hypoxia both induce a posttranslational modification (or loss of one) in HIF-1 that affects its binding to VHL. We propose that dynamic, site-specific interaction of HIF-1 with VHL provides one mechanism by which HIF-1 can be regulated.

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