Requirement for aspartate-cleaved bid in apoptosis signaling by DNA-damaging anti-cancer regimens

Werner, A.B., Tait, S.W.G. , de Vries, E., Eldering, E. and Borst, J. (2004) Requirement for aspartate-cleaved bid in apoptosis signaling by DNA-damaging anti-cancer regimens. Journal of Biological Chemistry, 279(27), pp. 28771-28780. (doi: 10.1074/jbc.M400268200)

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Lymphoid malignancies can escape from DNA-damaging anti-cancer drugs and gamma-radiation by blocking apoptosis-signaling pathways. How these regimens induce apoptosis is incompletely defined, especially in cells with nonfunctional p53. We report here that the BH3-only Bcl-2 family member Bid is required for mitochondrial permeabilization and apoptosis induction by etoposide and gamma-radiation in p53 mutant T leukemic cells. Bid is not transcriptionally up-regulated in response to these stimuli but is activated by cleavage on aspartate residues 60 and/or 75, which are the targets of caspase-8 and granzyme B. Bid activity is not inhibitable by c-Flip(L), CrmA, or dominant negative caspase-9 and therefore is independent of inducer caspase activation by death receptors or the mitochondria. Caspase-2, which has been implicated as inducer caspase in DNA damage pathways, appeared to be processed in response to etoposide and gamma-radiation but downstream of caspase-9. Knock down of caspase-2 by short interfering RNA further excluded its role in Bid activation by DNA damage. Caspase-2 was implicated in the death receptor pathway however, where it contributed to effector caspase processing downstream of inducer caspases. Granzyme B-specific serpins could not block DNA damage-induced apoptosis, excluding a role for granzyme B in the generation of active Bid. We conclude that Bid, cleaved by an undefined aspartate-specific protease, can be a key mediator of the apoptotic response to DNA-damaging anticancer regimens.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Tait, Professor Stephen
Authors: Werner, A.B., Tait, S.W.G., de Vries, E., Eldering, E., and Borst, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:26 April 2004

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