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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
Published on: September 16, 2017
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
Summary
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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