OS-9 Interacts with Hypoxia-inducible Factor 1(alpha) and Prolyl Hydroxylases to Negatively Regulate HIF-1 Activity

Hypoxia-inducible factor 1 (HIF-1) functions as a master regulator of oxygen homeostasis in metazoan species and mediates changes in gene transcription in response to changes in cellular oxygenation. The half-life of the HIF-1a subunit is determined by oxygen dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1a for ubiquitination and degradation. JHU researchers have demonstrated that the protein OS-9 interacts with both HIF-1a and HIF-1a prolyl hydroxylases. OS-9 gain-of-function promotes HIF-1a hydroxylation, VHL binding, proteasomal degradation of HIF-1a, and inhibition of HIF-1 mediated transcription. OS-9 loss-of-function increases HIF-1a protein levels, HIF-1-mediated transcription, and VEGF mRNA expression under nonhypoxic conditions. These data indicate that OS-9 is an essential component of a multi-protein complex that regulates HIF-1a levels in an O2-dependent manner. Description (Set) Proposed Use (Set) Induction or overexpression of OS-9 inhibits HIF-1 activity and may have therapeutic utility in cancer or other disease states associated with increased angiogenesis. Inhibition of OS-9 activity increases HIF-1 activity and may therapeutic utility in ischemic cardiovascular disease or other diseases in which angiogenesis is impaired Patent (Set) WO 2006/009843

Inventor(s): Pauline Callinan

Type of Offer: Licensing



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