Article abstract


Nature Cell Biology 2, 423 - 427 (2000)
Published online: 9 June 2000 | doi:10.1038/35017054

Ubiquitination of hypoxia-inducible factor requires direct binding to the bold beta-domain of the von Hippel–Lindau protein

Michael Ohh1, Cheol Won Park1,2, Mircea Ivan1, Michael A. Hoffman1, Tae-You Kim1,2, L. Eric Huang3, Nikola Pavletich2,4, Vincent Chau5 & William G. Kaelin1,2


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 beta-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an alpha-domain-dependent manner. This is the first function to be ascribed to the pVHL beta-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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  1. Department of Medicine, Brigham and Womens Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
  2. Howard Hughes Medical Institute
  3. Division of Hematology, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  4. Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
  5. Department of Cellular and Molecular Physiology, Pennsylvania State University School of Medicine, Hershey, Pennsylvania 17033, USA

Correspondence to: William G. Kaelin1,2 e-mail: william_kaelin@dfci.harvard.edu




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