期刊
NEOPLASIA
卷 8, 期 11, 页码 956-963出版社
NEOPLASIA PRESS
DOI: 10.1593/neo.06520
关键词
CuI2; NEDD8; UbcH5a; HIF alpha; VHL
类别
ECV is an E3 ubiquitin ligase complex, which is composed of elongins B and C, Rbx1, Cul2, and the substrate-conferring von Hippel-Lindau (VHL) tumor-suppressor protein that targets the catalytic A subunit of hypoxia-inducible factor (HIF) for oxygen-dependent ubiquitin-mediated destruction. Mutations in VHL that compromise proper HIF alpha regulation through ECV have been documented in the majority of renal cell carcinomas, underscoring the significance of the VHL-HIF pathway in renal epithelial oncogenesis. Recent evidence has shown that the modification of Cul2 by the ubiquitin-like molecule NEDD8 increases the activity of ECV to ubiquitylate HIF alpha. However, the underlying mechanism responsible for the NEDD8-mediated induction of ECV function is unknown. Here, we demonstrate that oxygen-dependent recognition of HIF alpha by VHL triggers Rbx1-dependent neddylation of Cul2, which preferentially engages the E2 ubiquitin-conjugating enzyme UbcH5a. These events establish a central role for the neddylation of Cul2 in a previously unrecognized, temporally coordinated activation of ECV with the recruitment of its substrate HIF alpha.
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