Under normoxic conditions the alpha-subunit of hypoxia-inducible factor (HIF-1alpha) 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-1alpha. This design enables procaspase-3 to be regulated similarly with HIF-1alpha, 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 VHL-mediated protein destruction motif of HIF-1alpha endowed procaspase-3 with hypoxia-specific cytotoxicity.

译文

在常氧条件下,缺氧诱导因子(HIF-1alpha)蛋白的α亚基被von Hippel-Lindau(VHL)肿瘤抑制蛋白作为E3泛素连接酶降解。最近,我们开发了一种低氧靶向蛋白TOP3,该蛋白由具有HIF-1alpha的VHL介导的蛋白破坏基序的procaspase-3组成。这种设计使procaspase-3与HIF-1alpha相似,在常氧下降解,而在低氧下稳定。此外,稳定化的TOP3被低氧应激诱导的内源性半胱天冬酶裂解,因此procaspase-3特别是在低氧条件下转化为活性caspase-3。这些数据表明,HIF-1α的VHL介导的蛋白质破坏基序赋予了procaspase-3具有缺氧特异性细胞毒性。

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