Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor ?.

ABSTRACT: pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxia-inducible factor ? (HIF-?) for proteasomal degradation. Although HIF-? activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-? alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-?-independent pathway in VHL pathogenesis. Here, we show that the transcription factor B-Myb is a pVHL substrate that is degraded via the ubiquitin-proteasome pathway and that vascular endothelial growth factor (VEGF)- and/or platelet-derived growth factor (PDGF)-dependent tyrosine 15 phosphorylation of B-Myb prevents its degradation. Mice injected with B-Myb knockdown 786-O cells developed dramatically larger tumors than those bearing control cell tumors. Microarray screening of B-Myb-regulated genes showed that the expression of HIF-?-dependent genes was not affected by B-Myb knockdown, indicating that B-Myb prevents HIF-?-dependent tumorigenesis through an HIF-?-independent pathway. These data indicate that the regulation of B-Myb by pVHL plays a critical role in VHL disease.

SUBMITTER: Okumura F 

PROVIDER: S-EPMC4907096 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature