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PMID: 17981124 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia.

Cell ·Vol. 131 ·No. 3 ·2007-11-02 ·Pages 584-95

Cheng J, Kang X, Zhang S, Yeh ET

Abstract

SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1(-/-) embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1(-/-) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.

MeSH Terms
Anemia/pathology Animals Apoptosis Cell Hypoxia Cysteine Endopeptidases Embryo, Mammalian/pathology Endopeptidases/deficiency,metabolism Erythroid Precursor Cells/cytology Erythropoiesis Erythropoietin/biosynthesis,genetics Fetus/cytology,metabolism Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Liver/cytology,metabolism Mice Mice, Knockout Models, Biological Proteasome Endopeptidase Complex/metabolism Protein Binding Protein Processing, Post-Translational Signal Transduction Thermodynamics Transcription, Genetic Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemicals
Hypoxia-Inducible Factor 1, alpha Subunit Erythropoietin Von Hippel-Lindau Tumor Suppressor Protein Endopeptidases Cysteine Endopeptidases Senp1 protein, mouse Proteasome Endopeptidase Complex
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cheng Jinke
Department of Cardiology, The University of Texas MD Anderson Cancer Center, The University of Texas, Houston Health Science Center, Houston, TX 77030, USA.
Kang Xunlei
Zhang Sui
Yeh Edward T H
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/j.cell.2007.08.045
Published
2007-11-02
Pages
584-95
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2128732
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA080089-05 · United States
NCI NIH HHS · R01 CA139520 · United States
NCI NIH HHS · R01 CA080089 · United States
NCI NIH HHS · R01 CA080089-01A1 · United States
NCI NIH HHS · R01 CA80089 · United States
NCI NIH HHS · R01 CA080089-02 · United States
NCI NIH HHS · R01 CA080089-03 · United States
NCI NIH HHS · CA16672 · United States
NCI NIH HHS · R01 CA080089-04 · United States
Corrections
CommentIn
PMID: 17981111
External Links
PubMed source DOI: 10.1016/j.cell.2007.08.045 PMC Full Text View journal details
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