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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Abstract

<jats:p>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.</jats:p>

Journal

  • FEBS Letters

    FEBS Letters 580 (24), 5718-5722, 2006-09-22

    Wiley

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