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First published online October 22, 2003
doi: 10.1242/10.1242/jcs.00829

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Bcl-2 on the endoplasmic reticulum: protecting the mitochondria from a distance

Departments of Medicine and Pharmacology, Comprehensive Cancer Center, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, OH 44106, USA

View larger version (29K): [in a new window]   Fig. 1. Alternative models of Bcl-2 family interactions. Left, anti-apoptotic Bcl-2 family members bind multi-domain pro-apoptotic family members (e.g. Bax), preventing them from inducing cytochrome c release. BH3-only proteins relieve this inhibition, freeing the multi-domain pro-apoptotic family members. Right, anti-apoptotic Bcl-2 family members bind to BH3-only proteins, thus preventing them from inducing Bax activity and cytochrome c release.

View larger version (19K): [in a new window]   Fig. 2. Potential model for the role of Bcl-2 on the ER. Bcl-2 on the ER sequesters activator BH3-only proteins, preventing them from interacting with Bax. Activator BH3-only proteins are displaced by sensitizer BH3-only proteins, freeing them to activate Bax and induce cytochrome c release.

View larger version (31K): [in a new window]   Fig. 3. The role of calcium ions in communicating death signals to mitochondria, and its regulation by Bcl-2. The ER lumen serves as a source of calcium ions that are released via InsP3 receptors. The resulting elevation of cytosolic calcium either directly mediates loss of mitochondrial permeability transition through increased uptake of calcium into the mitochondrial matrix, a process that is enhanced by permeabilization of the outer mitochondrial membrane by tcBid, or indirectly by activating calcineurin, which in turn activates Bad. Bcl-2 located on the ER membrane interferes with calcium-mediated apoptotic signals, either by decreasing ER lumenal calcium concentration (left) or by docking calcineurin to InsP3 receptors, thereby inhibiting InsP3-mediated calcium release and calcineurin-mediated dephosphorylation of Bad-P (right).