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Hydrogen peroxide signaling through tumor necrosis factor receptor 1 leads to selective activation of c-Jun

Cristen Pantano1, Punya Shrivastava, Brian McElhinney

  • 1Department of Pathology, University of Vermont, Burlington, Vermont 05405, USA.

The Journal of Biological Chemistry
|August 27, 2003
PubMed

Insights

Oxidative stress, like hydrogen peroxide (H2O2), disrupts tumor necrosis factor-alpha receptor 1 (TNF-R1) signaling. This imbalance inhibits inhibitor of kappaB kinase (IKK) while activating c-Jun N-terminal kinase (JNK), potentially promoting cell death.

Area of Science:

  • Cellular signaling
  • Oxidative stress biology
  • Molecular pathways

Background:

  • Tumor necrosis factor-alpha (TNFalpha) binding to TNF-R1 activates IKK and JNK pathways crucial for cell fate.
  • Hydrogen peroxide (H2O2) inhibits TNFalpha-induced IKK activation and independently triggers JNK activation and cell death in C10 cells.

Purpose of the Study:

  • To investigate the role of TNF-R1 in H2O2-induced JNK activation.
  • To elucidate the molecular mechanisms underlying H2O2's selective effects on IKK and JNK signaling.

Main Methods:

  • Utilized TNF-R1-deficient mouse lung fibroblasts and C10 cells expressing mutant TNF-R1.
  • Employed immunoprecipitation to analyze protein recruitment to TNF-R1.
  • Assessed protein expression levels of RIP, Hsp90, TRAF2, and JNK.

Main Results:

  • H2O2-induced JNK activation was significantly reduced in TNF-R1-deficient and mutant TNF-R1 cells.
  • H2O2 treatment led to the recruitment of TRADD, TRAF2, and JNK to TNF-R1.
  • RIP expression decreased, and Hsp90 was cleaved in H2O2-exposed cells, while TRAF2 expression remained unaffected.
  • Overexpression of TRAF2 activated JNK, explaining H2O2's selective JNK activation and IKK inhibition.

Conclusions:

  • Oxidative stress selectively impairs IKK activation via TNF-R1 while promoting JNK signaling.
  • This disruption of signaling pathways by oxidative stress creates an imbalance that may favor apoptosis.
  • TNF-R1 plays a critical role in mediating the cellular response to oxidative stress through JNK activation.

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