Differential role of glutaredoxin and thioredoxin in metabolic oxidative stress-induced activation of apoptosis signal-regulating kinase 1

Biochem J. 2003 Aug 1;373(Pt 3):845-53. doi: 10.1042/BJ20030275.


Redox-sensing molecules such as thioredoxin (TRX) and glutaredoxin (GRX) bind to apoptosis signal-regulating kinase 1 (ASK1) and suppress its activation. Glucose deprivation disrupted the interaction between TRX/GRX and ASK1 and subsequently activated the ASK1-stress-activated protein kinase/extracellular-signal-regulated kinase kinase-c-Jun N-terminal kinase 1 (JNK1) signal-transduction pathway. L-Buthionine-( S, R )-sulphoximine, which decreases intracellular glutathione content, enhanced glucose deprivation-induced activation of JNK1 by promoting the dissociation of TRX, but not GRX, from ASK1. Treatment of cells with exogenous glutathione disulphide ester resulted in the dissociation of GRX, but not TRX, from ASK1 and the subsequent activation of JNK1. Nonetheless, overexpression of calatase, an H(2)O(2) scavenger, inhibited JNK1 activation and cytotoxicity as well as the dissociation of TRX and GRX from ASK1 during combined glucose deprivation and L-buthionine-( S, R )-sulphoximine treatment. Taken together, glucose deprivation-induced metabolic oxidative stress may activate ASK1 through two different pathways: glutathione-dependent GRX-ASK1 and glutathione-independent TRX-ASK1 pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Buthionine Sulfoximine / pharmacology
  • Catalase / metabolism
  • Enzyme Activation
  • Genetic Vectors
  • Glucose / metabolism
  • Glutaredoxins
  • Humans
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases / metabolism*
  • Male
  • Oxidative Stress*
  • Oxidoreductases*
  • Proteins / physiology*
  • Thioredoxins / metabolism*
  • Tumor Cells, Cultured


  • GLRX protein, human
  • Glutaredoxins
  • Proteins
  • Buthionine Sulfoximine
  • Thioredoxins
  • Oxidoreductases
  • Catalase
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP3K5 protein, human
  • Glucose