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RESEARCH PAPER
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
Commitment of cells to apoptosis is governed largely by the interaction between members of the Bcl-2 protein family. Its three subfamilies have distinct roles: The BH3-only proteins trigger apoptosis by binding via their BH3 domain to prosurvival relatives, while the proapoptotic Bax and Bak have an essential downstream role involving permeabilization of organellar membranes and induction of caspase activation. We have investigated the regulation of Bak and find that, in healthy cells, Bak associates with Mcl-1 and Bcl-xL but surprisingly not Bcl-2, Bcl-w, or A1. These interactions require the Bak BH3 domain, which is also necessary for Bak dimerization and killing activity. When cytotoxic signals activate BH3-only proteins that can engage both Mcl-1 and Bcl-xL (such as Noxa plus Bad), Bak is displaced and induces cell death. Accordingly, the BH3-only protein Noxa could bind to Mcl-1, displace Bak, and promote Mcl-1 degradation, but Bak-mediated cell death also required neutralization of Bcl-xL by other BH3-only proteins. The results indicate that Bak is held in check solely by Mcl-1 and Bcl-xL and induces apoptosis only if freed from both. The finding that different prosurvival proteins have selective roles has notable implications for the design of anti-cancer drugs that target the Bcl-2 family.
[Keywords: Apoptosis; Bcl-2; Bcl-xL; Mcl-1; Bak; BH3-only]
Received February 9, 2005; revised version accepted April 14, 2005.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1304105.
1 These authors contributed equally to this work.
2 Corresponding author.
E-MAIL huang_d{at}wehi.edu.au; FAX 61-3-9347-0852.
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