Bid can mediate a pro-apoptotic response to etoposide and ionizing radiation without cleavage in its unstructured loop and in the absence of p53

Maas, C., de Vries, E., Tait, S.W.G. and Borst, J. (2011) Bid can mediate a pro-apoptotic response to etoposide and ionizing radiation without cleavage in its unstructured loop and in the absence of p53. Oncogene, 30(33), pp. 3636-3647. (doi: 10.1038/onc.2011.75)

Abstract

BH3-only protein Bid is a key player in death receptor-induced apoptosis, because it provides the link with the mitochondrial route for caspase activation. In this pathway, Bid is activated upon cleavage by caspase-8. Its BH3 domain-containing carboxy-terminal fragment subsequently provokes mitochondrial outer membrane permeabilization by Bak/Bax activation. Bid has also been implicated in the apoptotic response to ionizing radiation (IR) and the topoisomerase inhibitor etoposide, anti-cancer regimens that cause double-strand (ds)DNA breaks. We confirm the existence of this pathway and show that it is p53-independent. However, the degree of Bid participation in the apoptotic response to dsDNA breaks depends on the nature of cell transformation. We used Bid-deficient mouse embryonic fibroblast (MEF) lines that were reconstituted with Bid to control the cellular background and demonstrated that the Bid-dependent apoptotic pathway induced by IR and etoposide operates in MEFs that are transformed by SV40, but is not evident in E1A/Ras-transformed MEFs. The Bid-dependent apoptotic response in p53-deficient SV40-transformed MEFs contributed to clonogenic execution of the cells, implying relevance for treatment outcome. In these cells, Bid acted in a conventional manner in that it required its BH3 domain to mediate apoptosis in response to IR and etoposide, and triggered apoptotic execution by indirect activation of Bak/Bax, mitochondrial permeabilization and caspase-9 activation. However, the mechanism of Bid activation was unconventional, because elimination of all known or suspected cleavage sites for caspases or other proteolytic enzymes and even complete elimination of its unstructured cleavage loop left Bid's pro-apoptotic role in the response to IR and etoposide unaffected.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tait, Professor Stephen
• Authors: Maas, C., de Vries, E., Tait, S.W.G., and Borst, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogene
• ISSN: 0950-9232
• ISSN (Online): 1476-5594
• Published Online: 21 March 2011