Abstract
Tumor necrosis factor (TNFα) receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-κB and the kinase, JNK. While activation of caspase 8 is required for TNFα-induced apoptosis, and induction of NF-κB inhibits cell death, the precise function of JNK activation in TNFα signaling is not clearly understood. Here, we report that TNFα-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation of jBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP1 complex. We propose that the JNK pathway described here is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. Further, our findings define a mechanism for crosstalk between intrinsic and extrinsic cell death pathways.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 61-70 |
| Number of pages | 10 |
| Journal | Cell |
| Volume | 115 |
| Issue number | 1 |
| DOIs | |
| State | Published - Oct 3 2003 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank Dr. H. Zheng and members of her laboratory at Baylor College of Medicine and Dr. Bing Su at MD Anderson Cancer Center for helpful discussions. We also thank Dr. B. Vogelstein at Johns Hopkins Medical School for providing HCT116 cells; Dr. P. Chiao at M.D. Anderson Cancer Center for p65 −/− cells; and Dr. Xiaoming Yin at University of Pittsburgh for Bid −/− MEFs. Dr. R. Agami at Netherlands Cancer Institute for providing pSUPER; Dr. Rennefahrt and Dr. Rapp at University of Wuerzburg in Germany for pMKK7-JNK-wt and -kd plasmids; Dr. Hunter at Children's Hospital of Eastern in Ontario, Canada, for Ub-Smac and Ub-ΔAVPI-Smac cDNA; and Dr. C. Vincenz at University of Michigan for FADD-DN cDNA. Also, we thank Dr. J. Yuan at Harvard Medical School for Bid, tBid cDNA. This work was supported by grants from NCI (to X.W.).
