Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein (original) (raw)

Nature Cell Biology volume 2, pages 423–427 (2000)Cite this article

Abstract

von Hippel–Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel–Lindau protein (pVHL). Here we show that pVHL, through its β-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an α-domain-dependent manner. This is the first function to be ascribed to the pVHL β-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease.

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Acknowledgements

We thank C. Stebbins for purified pVHL/elongin C/elongin B complexes and H. Franklin Bunn and M. Meyerson for critical reading of the manuscript. This work was supported by grants from the NIH and from the Murray Foundation. M.O. is a Fellow of the National Cancer Institute of Canada. W.G.K. is a Howard Hughes Medical Institute assistant investigator.

Correspondence and requests for materials should be addressed to W.G.K.

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Authors and Affiliations

  1. Department of Medicine, Brigham and Womens Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, 02115, USA
    Michael Ohh, Cheol Won Park, Mircea Ivan, Michael A. Hoffman, Tae-You Kim & William G. Kaelin
  2. Howard Hughes Medical Institute,
    Cheol Won Park, Tae-You Kim, Nikola Pavletich & William G. Kaelin
  3. Division of Hematology, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA
    L. Eric Huang
  4. Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, USA
    Nikola Pavletich
  5. Department of Cellular and Molecular Physiology, Pennsylvania State University School of Medicine, Hershey, Pennsylvania, 17033, USA
    Vincent Chau

Authors

  1. Michael Ohh
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  2. Cheol Won Park
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  3. Mircea Ivan
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  4. Michael A. Hoffman
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  5. Tae-You Kim
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  6. L. Eric Huang
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  7. Nikola Pavletich
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  8. Vincent Chau
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  9. William G. Kaelin
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Correspondence toWilliam G. Kaelin.

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Ohh, M., Park, C., Ivan, M. et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein.Nat Cell Biol 2, 423–427 (2000). https://doi.org/10.1038/35017054

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