| Budget Amount *help |
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2015: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2013: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
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| 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.
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