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J. Biol. Chem., Vol. 279, Issue 27, 28771-28780, July 2, 2004

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Requirement for Aspartate-cleaved Bid in Apoptosis Signaling by DNA-damaging Anti-cancer Regimens^*

Arlette B. Werner, Stephen W. G. Tait, Evert de Vries, Eric Eldering¶, and Jannie Borst||

From the Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam and ^¶Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1100 DD Amsterdam, The Netherlands

Lymphoid malignancies can escape from DNA-damaging anti-cancer drugs and -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 -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 -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.

Received for publication, January 12, 2004 , and in revised form, April 23, 2004.

^* This work was supported by grants from the Dutch Cancer Foundation and by a Marie Curie fellowship from the European Community (to S. W. G. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplementary figure.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel.: 31-20-5122056; Fax: 31-20-5122057; E-mail: j.borst{at}nki.nl.

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