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 
-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
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 
-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.
- Department of Medicine, Brigham and Womens Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
- Howard Hughes Medical Institute
- Division of Hematology, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
- Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
- 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
