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Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals.

Human glutathione S-transferase P1-1 (GSTP1-1) is an ubiquitously expressed protein that plays an important role in the detoxification and xenobiotics metabolism. It has been shown that GSTP1-1 interacts with c-Jun NH(2)-terminal kinase (JNK) and suppresses its activity. Here, we report a novel function of GSTP1-1 in regulating tumor necrosis factor-alpha (TNF-alpha)-triggered signaling. The present experiments showed that GSTP1-1 physically associated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in vivo and in vitro. Overexpression of GSTP1-1 inhibited TRAF2-induced activation of both JNK and p38 but not of nuclear factor-kappaB (NF-kappaB). Glutathione S-transferase P1-1 also attenuated TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and inhibited TRAF2-ASK1-induced cell apoptosis by suppressing the interaction of TRAF2 and ASK1. Conversely, silencing of GSTP1-1 expression through RNA interference (RNAi) resulted in increase of TNF-alpha-dependent TRAF2-ASK1 association followed by hyper-activation of ASK1 and JNK. A mutant GSTP1-1 lacking TRAF domain-binding motif exhibited a significant decline of capacity to bind TRAF2 and block TRAF2-ASK1 signaling compared with the wild type of GSTP1-1. Moreover, the glutathione-conjugating activity of GSTP1-1 was not involved in the regulation of TRAF2 signaling. These findings indicate that GSTP1-1 plays an important regulatory role in TNF-alpha-induced signaling by forming ligand-binding interactions with TRAF2, which provides a new insight for analysing the protective effects of GSTP1-1 in tumor cells.

Pubmed ID: 16636664


  • Wu Y
  • Fan Y
  • Xue B
  • Luo L
  • Shen J
  • Zhang S
  • Jiang Y
  • Yin Z



Publication Data

September 21, 2006

Associated Grants


Mesh Terms

  • Cell Line
  • DNA Primers
  • Glutathione S-Transferase pi
  • HeLa Cells
  • Humans
  • Kidney
  • Kinetics
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase Kinase 5
  • Mutagenesis, Site-Directed
  • Recombinant Proteins
  • Signal Transduction
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha