Negative regulation of hypoxia inducible factor 1 by OS-9

摘要

The present invention discloses that OS-9 interacts with both HIF-1a and HIF-1a prolyl hydroxylases. Overexpression of OS-9 promotes the hydroxylation of HIF-1a, HIF-1a binding to VHL, proteasomal degradation of HIF-1a, and loss of HIF-1-mediated transcription. OS-9 loss-of-function increases HIF-1a protein levels and HIF-1-mediated transcription under non-hypoxic conditions. These data indicate that OS-9 is an essential component of a multiprotein complex that regulates HIF-1a protein levels in an O₂ dependent manner. Agents which modulate this complex, and methods to identify such agents, are disclosed.