TY - JOUR
T1 - Parallel regulation of von Hippel-Lindau disease by pVHL-mediated degradation of B-Myb and hypoxia-inducible factor α
AU - Okumura, Fumihiko
AU - Uematsu, Keiji
AU - Byrne, Stuart D.
AU - Hirano, Mie
AU - Joo-Okumura, Akiko
AU - Nishikimi, Akihiko
AU - Shuin, Taro
AU - Fukui, Yoshinori
AU - Nakatsukasa, Kunio
AU - Kamura, Takumi
N1 - Publisher Copyright:
© 2016, American Society for Microbiology.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.00067-16
DO - 10.1128/MCB.00067-16
M3 - Article
C2 - 27090638
AN - SCOPUS:84971384478
SN - 0270-7306
VL - 36
SP - 1803
EP - 1817
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 12
ER -