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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.

Original publication

DOI

10.1016/j.molcel.2005.01.011

Type

Journal article

Journal

Mol Cell

Publication Date

18/02/2005

Volume

17

Pages

503 - 512

Keywords

Carcinoma, Hepatocellular, Cell Hypoxia, Cells, Cultured, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Lectins, 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