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

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes th e familial cancer syndrome. VHL disease, characterized by a predisposition to renal cell carcinoma and other tumor types. Loss of VHL gene function al so is found in a majority of sporadic renal carcinomas. A preponderance of the tumor-disposing inherited missense mutations detected in VHL disease ar e within the elongin-binding domain of VHL. This region mediates the format ion of a multiprotein VHL complex containing elongin B. elongin C. cul-2. a nd Rbx1. This VHL complex is thought to function as an E3 ubiquitin ligase. Here, we report that VHL proteins harboring mutations which disrupt elongi n binding are unstable and rapidly degraded by the proteasome. In contrast, wild-type VHL proteins are directly stabilized by associating with both el ongins 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 o f elongin binding causes tumorigenesis by compromising VHL protein stabilit y and/or potential VHL ubiquitination functions.