Journal
FEBS LETTERS
Volume 580, Issue 24, Pages 5718-5722Publisher
WILEY
DOI: 10.1016/j.febslet.2006.09.025
Keywords
hypoxia-inducible factor-1; von Hippel-Lindau; caspase-3; hypoxia; apoptosis
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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.
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