BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program

Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 33.61). 12/2010; 330(6009):1390-3. DOI: 10.1126/science.1190217
Source: PubMed


Although the proteins BAX and BAK are required for initiation of apoptosis at the mitochondria, how BAX and BAK are activated
remains unsettled. We provide in vivo evidence demonstrating an essential role of the proteins BID, BIM, and PUMA in activating
BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c–mediated activation of caspases in response to
diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. Thus, many forms of
apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.

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Available from: Osamu Takeuchi, Aug 12, 2014
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    • "Deletion of any single BH3-only gene in mice, on the other hand, does not result in obvious developmental defects (Ren et al., 2010; Villunger et al., 2011), although Bid deletion inhibits Fas-induced apoptosis in certain cell types (Yin et al., 1999). Intriguingly, mice with Bid, Bim, and Puma triple knockout showed embryonic lethality, and a subset of the viable triple null mice displayed similar developmental defects to those of Bax-/-Bak-/-mice with persistent interdigital webs of skin on their feet and imperforate vaginas, indicating these three BH3-only proteins in combination are essential for Bak/Bax activation (Ren et al., 2010; Villunger et al., 2011). "
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    • "In our study, we investigated expression levels for three apoptosis-related genes and found significant changes in RARA and BBC3. In general, BBC3 is involved in BAX-dependent cell death related to developing retina and brain [59] but in the adult nervous system the cell death process is mediated by BIM. BBC3 expression can be altered in response to various insults and is involved in adult retinal cell degeneration [60]–[62]. "
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    • "Thus, upregulation of anti-apoptotic Bcl-2 proteins and/or down-regulation of pro-apoptotic proteins can confer resistance to apoptotic stimuli on tumor cells [3], [4]. Indeed, one or more of these anti-apoptotic Bcl-2 proteins is overexpressed in human cancers, resulting in resistance to chemotherapy and radiation [4], [5], [6], [7], [8], [9], [10]. Therefore, pharmacological inhibition of one or more of these anti-apoptotic Bcl-2 family proteins has been pursued as a novel cancer therapeutic strategy with the goal of overcoming apoptosis resistance of tumor cells. "
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