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Mechanism of hypoxia‐specific cytotoxicity of procaspase‐3 fused with a VHL‐mediated protein destruction motif of HIF‐1α containing Pro564
Author(s) -
Harada Hiroshi,
Kizaka-Kondoh Shinae,
Hiraoka Masahiro
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.09.025
Subject(s) - ubiquitin ligase , ubiquitin , hypoxia inducible factor 1 , hypoxia (environmental) , cytotoxicity , apoptosis , microbiology and biotechnology , caspase , protein subunit , chemistry , hypoxia inducible factors , protein degradation , cancer research , biology , biochemistry , programmed cell death , downregulation and upregulation , in vitro , gene , organic chemistry , oxygen
Under normoxic conditions the alpha‐subunit of hypoxia‐inducible factor (HIF‐1α) 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‐1α. This design enables procaspase‐3 to be regulated similarly with HIF‐1α, 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‐1α endowed procaspase‐3 with hypoxia‐specific cytotoxicity.