Parallel regulation of von Hippel-Lindau disease by pVHL-mediated degradation of B-Myb and hypoxia-inducible factor α

Fumihiko Okumura, Keiji Uematsu, Stuart D. Byrne, Mie Hirano, Akiko Joo-Okumura, Akihiko Nishikimi, Taro Shuin, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura

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pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxiainducible factor α (HIF-α) for proteasomal degradation. Although HIF-α activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-α alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-α-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-α-dependent genes was not affected by B-Myb knockdown, indicating that B-Myb prevents HIF-α-dependent tumorigenesis through an HIF-α-independent pathway. These data indicate that the regulation of B-Myb by pVHL plays a critical role in VHL disease.

Original languageEnglish
Pages (from-to)1803-1817
Number of pages15
JournalMolecular and cellular biology
Issue number12
Publication statusPublished - Jun 1 2016


All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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