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VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha.

Hypoxia-inducible factor (HIF)-1alpha is a short-lived protein and is ubiquitinated and degraded through the von Hippel-Lindau protein (pVHL)-E3 ubiquitin ligase pathway at normoxia. Deubiquitination, by reversing ubiquitination, has been recognized as an important regulatory step in ubiquitination-related processes. Here, we show that pVHL-interacting deubiquitinating enzyme 2, VDU2, but not VDU1, interacts with HIF-1alpha. VDU2 can specifically deubiquitinate and stabilize HIF-1alpha and, therefore, increase expression of HIF-1alpha targeted genes, such as vascular endothelial growth factor (VEGF). These findings suggest that ubiquitination of HIF-1alpha is a dynamic process and that ubiquitinated HIF-1alpha might be rescued from degradation by VDU2 through deubiquitination. Although pVHL functions as a master control for HIF-1alpha stabilization, as pVHL-E3 ligase mediates the ubiquitination of both HIF-1alpha and VDU2, the balance between the pVHL-mediated ubiquitination and VDU2-mediated deubiquitination of HIF-1alpha provides another level of control for HIF-1alpha stabilization.

Pubmed ID: 15776016

Authors

  • Li Z
  • Wang D
  • Messing EM
  • Wu G

Journal

EMBO reports

Publication Data

April 5, 2005

Associated Grants

None

Mesh Terms

  • Animals
  • COS Cells
  • Cercopithecus aethiops
  • Endopeptidases
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Luciferases
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase
  • Ubiquitin-Protein Ligases
  • Ubiquitins
  • Von Hippel-Lindau Tumor Suppressor Protein