OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha.

Hypoxia-inducible factor 1 (HIF-1) functions as a master regulator of oxygen homeostasis in metazoan species. HIF-1 mediates changes in gene transcription in response to changes in cellular oxygenation. The half-life of the HIF-1alpha 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-1alpha for ubiquitination and degradation. Here, we demonstrate that OS-9, the protein product of a widely expressed gene, interacts with both HIF-1alpha and HIF-1alpha prolyl hydroxylases. OS-9 gain-of-function promotes HIF-1alpha hydroxylation, VHL binding, proteasomal degradation of HIF-1alpha, and inhibition of HIF-1-mediated transcription. OS-9 loss-of-function caused by RNA interference increases HIF-1alpha 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 multiprotein complex that regulates HIF-1alpha levels in an O2-dependent manner.
Mesh Terms:
Carcinoma, Hepatocellular, Cell Hypoxia, Cells, Cultured, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Liver Neoplasms, Neoplasm Proteins, Oxygen, Procollagen-Proline Dioxygenase, Proteasome Endopeptidase Complex, Protein Binding, RNA Interference, RNA, Messenger, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Vascular Endothelial Growth Factor A, Von Hippel-Lindau Tumor Suppressor Protein
Mol. Cell
Date: Feb. 18, 2005
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