Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 15, Pages 8507-8512Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.15.8507
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Funding
- NCI NIH HHS [P30 CA013330, CA 13330] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007110, DK 07218, DK 07110, T32 DK007218] Funding Source: Medline
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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.
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