Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1

We report that Trx is a physiological inhibitor of ASK1

M. Saitoh


Scholarcy highlights

  • Apoptosis plays an essential role in animal development, homeostasis and the pathogenesis of multiple diseases including cancer, infectious and neurodegenerative disorders
  • Two-hybrid screen for ASK1-interacting proteins We employed the yeast two-hybrid system to search for proteins that bind to ASK1, using LexA DNA-binding domain ASK1-K709R as bait
  • Our findings suggest that Trx is a physiological inhibitor of ASK1
  • Given that Trx is highly susceptible to Reactive oxygen species-induced oxidation and that ROS rapidly induce translocation of Trx into the nucleus, ROS generated by cytokine or stress may oxidize and remove Trx from pre-existing Trx–ASK1 complexes, leading to the activation of ASK1 and the subsequent ASK1-dependent apoptosis signaling cascade
  • Antioxidants including Nac might prevent apoptosis at least in part by inhibiting oxidation-induced dissociation of Trx from ASK1. It is still unclear whether serum withdrawal- and tumor necrosis factor-α-induced activation of ASK1 are primarily mediated by intracellular redox changes including generation of ROS
  • It has been thought that ROS may lack biological specificity as signaling intermediates, our model might associate ROS with signaling specificity in that ROS may target the specific interaction between Trx and ASK1
  • A fraction of the whole cell lysate was analyzed by immunoblotting using anti-Trx antibody to determine the level of expression of Trx. In vitro binding assay glutathione S-transferase constructs for Trx were prepared in pGEX-4T-1 vector

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