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Determination of the Relative Potency of an Anti-TNF Monoclonal Antibody (mAb) by Neutralizing TNF Using an In Vitro Bioanalytical Method
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A JNK-dependent pathway is required for TNFalpha-induced apoptosis

Yibin Deng1, Xiaoyang Ren, Lin Yang

  • 1Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 70030, USA.

Cell
|October 9, 2003
PubMed

Insights

Tumor necrosis factor (TNFalpha) signaling activates JNK, which cleaves Bid. This releases Smac/DIABLO, relieving inhibition and enabling caspase 8 activation for apoptosis.

Area of Science:

  • Cellular signaling pathways
  • Apoptosis and cell death mechanisms
  • Molecular biology of TNFalpha signaling

Background:

  • Tumor necrosis factor-alpha (TNFalpha) receptor signaling activates multiple downstream effectors, including caspase 8, NF-kappaB, and JNK.
  • While caspase 8 is essential for TNFalpha-induced apoptosis and NF-kappaB inhibits cell death, the role of JNK in this pathway remains unclear.

Purpose of the Study:

  • To elucidate the precise function of JNK activation in TNFalpha-mediated apoptosis.
  • To define the sequential pathway linking JNK activation to caspase 8 cleavage and cell death.

Main Methods:

  • Investigated the role of JNK, Bid, and Smac/DIABLO in TNFalpha signaling using molecular biology techniques.
  • Analyzed caspase 8 cleavage, Bid cleavage product generation (jBid), and mitochondrial release of proteins.
  • Examined the disruption of the TRAF2-cIAP1 complex by Smac/DIABLO.

Main Results:

  • TNFalpha-mediated apoptosis requires a sequential pathway involving JNK, Bid, and Smac/DIABLO.
  • JNK activation leads to caspase 8-independent cleavage of Bid, generating jBid.
  • jBid translocation to mitochondria results in Smac/DIABLO release, which disrupts the TRAF2-cIAP1 complex.

Conclusions:

  • The JNK pathway is essential for relieving TRAF2-cIAP1-mediated inhibition of caspase 8 activation and apoptosis.
  • This study reveals a novel mechanism of crosstalk between intrinsic and extrinsic cell death pathways.
  • Findings provide new insights into the regulation of TNFalpha-induced cell death.

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