Medical College of Wisconsin
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Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein. Cancer Res 2001 May 15;61(10):4136-42

Date

05/19/2001

Pubmed ID

11358837

Scopus ID

2-s2.0-0035872479   74 Citations

Abstract

Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that plays a critical role in regulating genes involved in erythropoiesis and angiogenesis. Recent evidence indicates that the von Hippel-Lindau tumor suppressor protein (VHL) is part of a ubiquitin ligase complex that promotes the degradation of HIF-1alpha under normoxic conditions. Under hypoxic conditions, HIF-1alpha is markedly stabilized. A critical issue in understanding the hypoxic response is the identification of hypoxia-regulated steps. We show here that hypoxia and cobalt treatment modulate the capacity of a HIF-1alpha fragment comprising residues 531-652 to coimmunoprecipitate with VHL. Hypoxia and cobalt both significantly diminish the interaction, and furthermore, normoxia treatment after hypoxia rapidly normalizes it. This HIF-1alpha fragment confers hypoxia and cobalt inducibility on a heterologous protein. Significantly, contained within this fragment is a short 27-residue sequence that behaves identically in all respects noted above. Finally, evidence is provided to show that cobalt and hypoxia both induce a posttranslational modification (or loss of one) in HIF-1alpha that affects its binding to VHL. We propose that dynamic, site-specific interaction of HIF-1alpha with VHL provides one mechanism by which HIF-1alpha can be regulated.

Author List

Yu F, White SB, Zhao Q, Lee FS

Author

Sarah B. White MD, MS, FSIR, FCIRSE Vice Chair, Professor in the Radiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Binding Sites
COS Cells
Cell Hypoxia
Cobalt
DNA-Binding Proteins
Fungal Proteins
HeLa Cells
Humans
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Immunoblotting
Ligases
Molecular Sequence Data
Nuclear Proteins
Precipitin Tests
Proteins
Recombinant Fusion Proteins
Saccharomyces cerevisiae Proteins
Sequence Homology, Amino Acid
Substrate Specificity
Transcription Factors
Transfection
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases
Von Hippel-Lindau Tumor Suppressor Protein