A JNK-Dependent Pathway Is Required for TNFα-Induced Apoptosis

JNK contributes to TNF␣-mediated apoptosis remains Molecular and Cellular Biology to be addressed. Baylor College of Medicine The intrinsic apoptotic pathway is the result of activa-Houston, Texas 70030 tion of mitochondria-mediated cell death events, including changes in mitochondrial membrane permeability and subsequent release of proapoptotic factors in-Summary volved in various aspects of apoptosis (Wang, 2001).and induction of NF-␬B inhibits cell death, the precise clease G (Li et al., 2001). Cytosolic cyto c and Apaf-1 function of JNK activation in TNF␣ signaling is not form an essential part of apoptosis complex and lead clearly understood. Here, we report that TNF␣-medi-to the activation of caspase 9, which then processes and ated caspase 8 cleavage and apoptosis require a se-activates other caspases to orchestrate the biochemical quential pathway involving JNK, Bid, and Smac/DIA-execution of cells (Li et al., 1997). BLO. Activation of JNK induces caspase 8-independent Although the apoptotic pathways through death re-cleavage of Bid at a distinct site to generate the Bid ceptors and mitochondria are capable of operating inde-cleavage product jBid. Translocation of jBid to mito-pendently, accumulating evidence suggests that a chondria leads to preferential release of Smac/DIABLO, crosstalk exists between the two pathways. One link but not cytochrome c. The released Smac/DIABLO then between death receptor signaling and mitochondrial disrupts the TRAF2-cIAP1 complex. We propose that pathway comes from the finding that the BH3-domain the JNK pathway described here is required to relieve only protein Bid is cleaved and activated by active cas-the inhibition imposed by TRAF2-cIAP1 on caspase pase 8. The truncated Bid (tBid) translocates to mito-8 activation and induction of apoptosis. Further, our chondria and triggers cyto c release (Li et al., 1998; Luo findings define a mechanism for crosstalk between et al., 1998). We have shown that caspase 8-Bid-Bax-intrinsic and extrinsic cell death pathways. depedent intrinsic pathway is required for TRAIL-and FasL-mediated apoptosis in human cancer cells (Deng Introduction et al., 2002). Studies on the function of mitochondria in TNF␣-Activation of death receptor TNFR1 (tumor necrosis fac-induced apoptosis have been complicated by the fact tor receptor 1) by TNF␣ leads to the recruitment of that TNF␣-induced apoptosis requires the inhibition of TNFR1-associated death domain protein (TRADD), NF-␬B. Most of previous studies achieved this by which serves as a platform to form various signaling blocking RNA or protein synthesis using actinomycin D complexes involved in different biological processes (Act D) or cyclohexamide (CHX), which inevitably affect (Baud and …