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Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals

Rong, Yi-Ping; Aromolaran, Ademuyiwa S.; Bultynck, Geert; Zhong, Fei; Li, Xiang; McColl, Karen; Matsuyama, Shigemi; Herlitze, Stephan; Roderick, H. Llewelyn; Bootman, Martin D.; Mignery, Gregory A.; Parys, Jan B.; De Smedt, Humbert and Distelhorst, Clark W. (2008). Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals. Molecular Cell, 31(2) pp. 255–265.

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The antiapoptotic protein Bcl-2 inhibits Ca2+ release from the endoplasmic reticulum (ER). One proposed mechanism involves an interaction of Bcl-2 with the inositol 1,4,5-trisphosphate receptor (IP3R) Ca2+ channel localized with Bcl-2 on the ER. Here we document Bcl-2-IP3R interaction within cells by FRET and identify a Bcl-2 interacting region in the regulatory and coupling domain of the IP3R. A peptide based on this IP3R sequence displaced Bcl-2 from the IP3R and reversed Bcl-2-mediated inhibition of IP3R channel activity in vitro, IP3-induced ER Ca2+ release in permeabilized cells, and cell-permeable IP3 ester-induced Ca2+ elevation in intact cells. This peptide also reversed Bcl-2's inhibition of T cell receptor-induced Ca2+ elevation and apoptosis. Thus, the interaction of Bcl-2 with IP3Rs contributes to the regulation of proapoptotic Ca2+ signals by Bcl-2, suggesting the Bcl-2-IP3R interaction as a potential therapeutic target in diseases associated with Bcl-2's inhibition of cell death.

Item Type: Journal Item
Copyright Holders: 2008 Elsevier Inc.
ISSN: 1097-4164
Keywords: cell cycle; signalling
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Health and Wellbeing PRA (Priority Research Area)
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Item ID: 34868
Depositing User: Martin Bootman
Date Deposited: 24 Oct 2012 13:09
Last Modified: 11 Sep 2017 15:32
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