title: Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products.
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.
authors.affiliation: Departments of Microbiology and Immunology, Marion Bessin Liver Research Center Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Schoenfeld
authors.forename: E J
authors.initials: EJ
authors.lastname: Davidowitz
authors.forename: R D
authors.initials: RD
authors.lastname: Burk
mesh_terms: D002461:Cell Line, Transformed; D003546:Cysteine Endopeptidases / Q000378:metabolism; D000075065:Elongin; D016147:Genes, Tumor Suppressor; D006801:Humans; D008025:Ligases; D009097:Multienzyme Complexes / Q000378:metabolism; D016296:Mutagenesis; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: C000616396:ELOB protein, human; C000616395:ELOC protein, human; D000075065:Elongin; D009097:Multienzyme Complexes; D011506:Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases; C497446:VHL protein, human