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Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.

In normoxic cells the hypoxia-inducible factor-1 alpha (HIF-1 alpha) is rapidly degraded by the ubiquitin-proteasome pathway, and activation of HIF-1 alpha to a functional form requires protein stabilization. Here we show that the product of the von Hippel-Lindau (VHL) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of HIF-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of HIF-1 alpha. The region of VHL mediating interaction with HIF-1 alpha overlapped with a putative macromolecular binding site observed within the crystal structure of VHL. This motif of VHL also represents a mutational hotspot in tumors, and one of these mutations impaired interaction with HIF-1 alpha and subsequent degradation. Interestingly, the VHL binding site within HIF-1 alpha overlapped with one of the minimal transactivation domains. Protection of HIF-1 alpha against degradation by VHL was a multistep mechanism, including hypoxia-induced nuclear translocation of HIF-1 alpha and an intranuclear hypoxia-dependent signal. VHL was not released from HIF-1 alpha during this process. Finally, stabilization of HIF-1 alpha protein levels per se did not totally bypass the need of the hypoxic signal for generating the transactivation response.

Pubmed ID: 10944113

Authors

  • Tanimoto K
  • Makino Y
  • Pereira T
  • Poellinger L

Journal

The EMBO journal

Publication Data

August 15, 2000

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Anoxia
  • Binding Sites
  • COS Cells
  • Cell Line
  • Crystallography, X-Ray
  • Cysteine Endopeptidases
  • DNA-Binding Proteins
  • Fungal Proteins
  • Green Fluorescent Proteins
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Ligases
  • Luminescent Proteins
  • Models, Biological
  • Molecular Sequence Data
  • Multienzyme Complexes
  • Mutation
  • Nuclear Proteins
  • Oxygen
  • Plasmids
  • Precipitin Tests
  • Proteasome Endopeptidase Complex
  • Protein Structure, Tertiary
  • Proteins
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transcription Factors
  • Transcriptional Activation
  • Transfection
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Ubiquitins
  • Von Hippel-Lindau Tumor Suppressor Protein