title: Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α.
abstract: pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxia-inducible 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.
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan okumura.fumihiko@a.mbox.nagoya-u.ac.jp z47617a@nucc.cc.nagoya-u.ac.jp.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Okumura
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Uematsu
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Byrne
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Hirano
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Joo-Okumura
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience and Research Center for Advanced Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.affiliation: Department of Urology, Kochi University, Kochi, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Shuin
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience and Research Center for Advanced Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nakatsukasa
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan okumura.fumihiko@a.mbox.nagoya-u.ac.jp z47617a@nucc.cc.nagoya-u.ac.jp.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kamura
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D046988:Proteasome Endopeptidase Complex; D015534:Trans-Activators; D014443:Tyrosine; D025801:Ubiquitin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C064352:MYBL2 protein, human; C497446:VHL protein, human