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

Jin Hyen Baek; Patrick C Mahon; Jane Oh; Brian Kelly; Balaji Krishnamachary; Mia Pearson; Denise A Chan; Amato J Giaccia; Gregg L Semenza

doi:10.1016/j.molcel.2005.01.011

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

Mol Cell. 2005 Feb 18;17(4):503-12. doi: 10.1016/j.molcel.2005.01.011.

Authors

Jin Hyen Baek¹, Patrick C Mahon, Jane Oh, Brian Kelly, Balaji Krishnamachary, Mia Pearson, Denise A Chan, Amato J Giaccia, Gregg L Semenza

Affiliation

¹ Institute for Cell Engineering, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

PMID: 15721254
DOI: 10.1016/j.molcel.2005.01.011

Abstract

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 / 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

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Lectins
Neoplasm Proteins
OS9 protein, human
RNA, Messenger
Transcription Factors
Tumor Suppressor Proteins
Vascular Endothelial Growth Factor A
Procollagen-Proline Dioxygenase
Ubiquitin-Protein Ligases
Von Hippel-Lindau Tumor Suppressor Protein
Proteasome Endopeptidase Complex
VHL protein, human
Oxygen