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, w...

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Bibliographic Details
Published in:Molecular cell 2005-02, Vol.17 (4), p.503-512
Main Authors: Baek, Jin Hyen, Mahon, Patrick C, Oh, Jane, Kelly, Brian, Krishnamachary, Balaji, Pearson, Mia, Chan, Denise A, Giaccia, Amato J, Semenza, Gregg L
Format: Article
Language:English
Subjects:
Carcinoma, Hepatocellular - metabolism
Cell Hypoxia
Cells, Cultured
Humans
Hydroxylation
Hypoxia-Inducible Factor 1, alpha Subunit
Lectins
Liver Neoplasms - metabolism
Neoplasm Proteins - metabolism
Oxygen - metabolism
Procollagen-Proline Dioxygenase - metabolism
Proteasome Endopeptidase Complex - metabolism
Protein Binding
RNA Interference
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
Tumor Suppressor Proteins - metabolism
Ubiquitin-Protein Ligases - metabolism
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
Von Hippel-Lindau Tumor Suppressor Protein
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Summary: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.
ISSN:1097-2765