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Mol Cell Biol. 2016 May 31;36(12):1803-17. doi: 10.1128/MCB.00067-16. Print 2016 Jun 15.

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

Author information

1
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.
2
Division of Biological Science, Graduate School of Science, Nagoya University, Aichi, Japan.
3
Division of Immunogenetics, Department of Immunobiology and Neuroscience and Research Center for Advanced Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
4
Department of Urology, Kochi University, Kochi, Japan.

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.

PMID:
27090638
PMCID:
PMC4907096
DOI:
10.1128/MCB.00067-16
[Indexed for MEDLINE]
Free PMC Article

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