TRAIL receptor and CD95 signal to mitochondria via FADD, Caspase-8/10, Bid, and Bax but differentially regulate events downstream from truncated Bid

Werner, A.B., de Vries, E., Tait, S.W.G. , Bontjer, I. and Borst, J. (2002) TRAIL receptor and CD95 signal to mitochondria via FADD, Caspase-8/10, Bid, and Bax but differentially regulate events downstream from truncated Bid. Journal of Biological Chemistry, 277(43), pp. 40760-40767. (doi:10.1074/jbc.M204351200)

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Publisher's URL: http://dx.doi.org/10.1074/jbc.M204351200

Abstract

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, FLIPL, or a Bid mutant lacking cleavage sites for caspase-8/10 completely inhibited Cyt crelease in response to either receptor. Depletion of Bid from TRAIL- or CD95-activated cytosols blocked their capacity to mediate Cytc 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tait, Professor Stephen
Authors: Werner, A.B., de Vries, E., Tait, S.W.G., Bontjer, I., and Borst, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:23 August 2002

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