Functiona analysis of tumor suppressor gene product pVHL

2015 Fiscal Year Final Research Report

• Project/Area Number: 25291023
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Nagoya University
• Principal Investigator: Kamura Takumi 名古屋大学, 理学(系)研究科(研究院), 教授 (40333455)
• Co-Investigator(Kenkyū-buntansha): Okumura Fumihiko 名古屋大学, 大学院理学研究科, 助教 (00507212)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: タンパク質分解

Outline of Final Research Achievements

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

Free Research Field

分子生物学