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PMID:17981124

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Citation

Cheng, J, Kang, X, Zhang, S and Yeh, ET (2007) SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 131:584-95

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.

Links

PubMed PMC2128732 Online version:10.1016/j.cell.2007.08.045

Keywords

Anemia/pathology; Animals; Apoptosis; Cell Hypoxia; Embryo, Mammalian/pathology; Endopeptidases/deficiency; Endopeptidases/metabolism; Erythroid Precursor Cells/cytology; Erythropoiesis; Erythropoietin/biosynthesis; Erythropoietin/genetics; Fetus/cytology; Fetus/metabolism; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Liver/cytology; Liver/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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:EPO

acts_upstream_of_or_within

GO:0033033: negative regulation of myeloid cell apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000038)
  • regulates_o_occurs_in:(EMAPA:16846)

Seeded From UniProt

complete

MOUSE:VHL

acts_upstream_of_or_within

GO:0010498: proteasomal protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(MGI:MGI:106918)

Seeded From UniProt

complete

MOUSE:SENP1

acts_upstream_of_or_within

GO:0016926: protein desumoylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SENP1

acts_upstream_of_or_within

GO:0032435: negative regulation of proteasomal ubiquitin-dependent protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3818522

P

  • regulates_o_occurs_in:(EMAPA:16846)

Seeded From UniProt

complete

MOUSE:SENP1

acts_upstream_of_or_within

GO:0010724: regulation of definitive erythrocyte differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3818522

P

  • regulates_o_occurs_in:(EMAPA:16846)

Seeded From UniProt

complete

HUMAN:HIF1A

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q9P0U3

P

Seeded From UniProt

complete

HUMAN:SENP1

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q16665

P

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q9P0U3

P

Seeded From UniProt

complete


See also

References

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