Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products

Alan R. Schoenfeld, Eliot J. Davidowitz, Robert D. Burk

Research output: Contribution to journalArticle

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Abstract

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the familial cancer syndrome, VHL disease, characterized by a predisposition to renal cell carcinoma and other tumor types. Loss of VHL gene function also is found in a majority of sporadic renal carcinomas. A preponderance of the tumor-disposing inherited missense mutations detected in VHL disease are within the elongin-binding domain of VHL. This region mediates the formation of a multiprotein VHL complex containing elongin B, elongin C, cul-2, and Rbx1. This VHL complex is thought to function as an E3 ubiquitin ligase. Here, we report that VHL proteins harboring mutations which disrupt elongin binding are unstable and rapidly degraded by the proteasome. In contrast, wild-type VHL proteins are directly stabilized by associating with both elongins B and C. In addition, elongins B and C are stabilized through their interactions with each other and VHL. Thus, the entire VHL/elongin complex is resistant to proteasomal degradation. Because the elongin-binding domain of VHL is frequently mutated in cancers, these results suggest that loss of elongin binding causes tumorigenesis by compromising VHL protein stability and/or potential VHL ubiquitination functions.

Original languageEnglish (US)
Pages (from-to)8507-8512
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number15
DOIs
StatePublished - Jul 18 2000

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Tumor Suppressor Genes
von Hippel-Lindau Disease
Neoplasms
Ubiquitin-Protein Ligases
Protein Stability
Ubiquitination
Missense Mutation
Proteasome Endopeptidase Complex
elongin
Renal Cell Carcinoma
Carcinogenesis
Proteins
Carcinoma
Kidney
Mutation
Genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. / Schoenfeld, Alan R.; Davidowitz, Eliot J.; Burk, Robert D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 15, 18.07.2000, p. 8507-8512.

Research output: Contribution to journalArticle

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