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 -domain of the von Hippel−Lindau proteinMichael 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, 21
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 should be addressed to William G. Kaelin william_kaelin@dfci.harvard.eduvon 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 -domain, binds directly to hypoxia-inducible factor
(HIF), thereby targeting HIF for ubiquitination in an -domain-dependent
manner. This is the first function to be ascribed to the pVHL -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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