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

Michael Ohh; Cheol Won Park; Mircea Ivan; Michael A. Hoffman; Tae You Kim; L. Eric Huang; Nikola Pavletich; Vincent Chau; William G. Kaelin

doi:10.1038/35017054

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

Michael Ohh, Cheol Won Park, Mircea Ivan, Michael A. Hoffman, Tae You Kim, L. Eric Huang, Nikola Pavletich, Vincent Chau, William G. Kaelin

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1345 Scopus citations

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.

Original language	English (US)
Pages (from-to)	423-427
Number of pages	5
Journal	Nature Cell Biology
Volume	2
Issue number	7
DOIs	https://doi.org/10.1038/35017054
State	Published - 2000

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Cell Biology

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title = "Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel - Lindau protein",

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.",

author = "Michael Ohh and Park, {Cheol Won} and Mircea Ivan and Hoffman, {Michael A.} and Kim, {Tae You} and Huang, {L. Eric} and Nikola Pavletich and Vincent Chau and Kaelin, {William G.}",

note = "Funding Information: 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.",

year = "2000",

doi = "10.1038/35017054",

language = "English (US)",

volume = "2",

pages = "423--427",

journal = "Nature Cell Biology",

issn = "1465-7392",

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T1 - Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel - Lindau protein

AU - Ohh, Michael

AU - Park, Cheol Won

AU - Ivan, Mircea

AU - Hoffman, Michael A.

AU - Kim, Tae You

AU - Huang, L. Eric

AU - Pavletich, Nikola

AU - Chau, Vincent

AU - Kaelin, William G.

N1 - Funding Information: 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.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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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Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel - Lindau protein

Abstract

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