Werner AB, de Vries E, Tait SW, Bontjer I, Borst J.. TRAIL receptor and CD95 signal to mitochondria via FADD, caspase-8/10, Bid, and Bax but differentially regulate events downstream from truncated Bid. J Biol Chem 277: 40760-40767

Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2002; 277(43):40760-7. DOI: 10.1074/jbc.M204351200
Source: PubMed


The death receptor ligand TRAIL arouses much interest for clinical application. We found that TRAIL receptor could induce cytochrome c (Cyt c) release from mitochondria in cells that failed to respond to CD95. Therefore, we examined whether these two closely related death receptors use different intermediates to convey the apoptotic signal to mitochondria. Dominant negative FADD, FLIP(L), or a Bid mutant lacking cleavage sites for caspase-8/10 completely inhibited Cyt c release in response to either receptor. Depletion of Bid from TRAIL- or CD95-activated cytosols blocked their capacity to mediate Cyt c release from mitochondria in vitro, whereas Bax depletion reduced it. We conclude that FADD, caspase-8/10, and caspase-cleaved Bid are required for TRAIL receptor and CD95 signaling to mitochondria, whereas Bax is a common accessory. In vitro, caspase-8 treatment of cytosol from CD95-resistant cells permitted generation of truncated Bid and its association with mitochondria. However, this cytosol impaired the ability of truncated Bid to liberate Cyt c from exogenous mitochondria. We conclude that the TRAIL receptor can bypass or neutralize the activity of cytosolic factor that blocks truncated Bid function. This may benefit the capacity of TRAIL to break apoptosis resistance in tumor cells.

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    • "Caspase-8 can be activated downstream of caspase-9, through caspases-3 and -6, independently of death receptor signalling [17-19,23]. Furthermore, caspase-8 can amplify the death signal by activating the mitochondrial pathway through the cleavage of the BH3-only protein Bid [14,24-30]. Cleaved Bid (tBid) translocates to the mitochondria and then triggers mitochondrial depolarization, leading to cytochrome c release and subsequent caspase-9 activation, by which the activation of caspase-8 initiates a positive feedback loop that amplifies the mitochondrial pathway. "
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    • "The BH3 family member Bid mediates the cross-talk between the extrinsic and intrinsic apoptotic pathways (Li et al., 1998). Earlier studies have shown that the overexpression of a dominant negative Bid construct inhibited apoptosis induced by both the Fas and TRAIL receptors in Jurkat cells (Werner et al., 2002), and Bid has been reported to regulate the synergy between TRAIL and epotoside in M28 and REN cells (Broaddus et al., 2005). We found that Bid is critical for FLIP silencing-induced processing of caspase 3 and cell death in the HCT116 and HT29 cells, indicating that mitochondrial activation is required for cell death to occur. "
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    • "In humans, caspase 10 is closely related to caspase 8. They both have been reported to be recruited and activated upon activation of transmembrane receptors of the TNF receptor family (Kischkel et al., 2001; Werner et al., 2002). In melanoma cells, we show that caspase 10 is expressed but is not proteolytically processed upon TRAIL exposure. "
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