Mechanism of hypoxia-specific cytotoxicity of procaspase-3 fused with a VHL-mediated protein destruction motif of HIF-1α containing Pro564
Mechanism of hypoxia-specific cytotoxicity of procaspase-3 fused with a VHL-mediated protein destruction motif of HIF-1α containing Pro564
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DOI：
10.1016/j.febslet.2006.09.025
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发表时间：
2006-10-16
期刊：
影响因子：
3.5
通讯作者：
Hiraoka, Masahiro
中科院分区：
文献类型：
--
作者：
Harada, Hiroshi;Kizaka-Kondoh, Shinae;Hiraoka, Masahiro
在规范条件下，围比氧诱导因子（HIF-1α）蛋白的α-亚基是由von Hippel-Lindau（VHL）抑制蛋白作为E3泛素蛋白抑制蛋白降解的靶向。最近，我们开发了一种靶向缺氧的蛋白质TOP3，该蛋白由procaspase-3组成，其中具有HIF-1 Alpha的VHL介导的蛋白质破坏基序。该设计使Procaspase-3与HIF-1α相似地调节，在低氧下稳定下，在正常氧下降解。此外，稳定的TOP3被低氧应激诱导的内源性caspase裂解，因此在低氧条件下专门将procaspase-3转换为活性caspase-3。这些数据表明，HIF-1 Alpha的VRL介导的蛋白质破坏基序具有缺氧特异性细胞毒性的procaspase-3。 （c）2006年欧洲生化社会联合会。由Elsevier B.V.保留所有权利。
Under normoxic conditions the alpha-subunit of bypoxia-inducible factor (HIF-1 alpha) protein is targeted for degradation by the von Hippel-Lindau (VHL) tumor suppressor protein acting as an E3 ubiquitin ligase. Recently, we developed a hypoxia-targeting protein, TOP3, which consisted of procaspase-3 with the VHL-mediated protein destruction motif of HIF-1 alpha. This design enables procaspase-3 to be regulated similarly with HIF-1 alpha, being degraded under normoxia while stabilized under hypoxia. Furthermore, stabilized TOP3 was cleaved by the hypoxic stress-induced endogenous caspases and thus the procaspase-3 was converted to active caspase-3 specifically under hypoxic conditions. These data demonstrated that the VRL-mediated protein destruction motif of HIF-1 alpha endowed procaspase-3 with hypoxia-specific cytotoxicity. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.