FIG. 1.

Pathways of extrinsic and intrinsic apoptosis, highlighting roles of Bcl-2 family members. The expression in β-cells of the various Bcl-2 family proteins listed is currently unknown, and their potential contributions are largely uncharacterized. The study of Grunnet et al. highlights a pathway leading from the IL-1 receptor (IL-1R) to the intrinsic apoptotic pathway mediated via dephosphorylation of the BH3-only protein Bad. Sequestering members of the prosurvival group of Bcl-2 proteins relieves inhibition of Bax/Bak leading to downstream caspase activation. Previous work has identified a role for cleavage of Bid downstream of the TNFR, thus defining a cross-talk mechanism between the extrinsic and instrinsic apoptotic pathways (8). How other known signals arising from IL-1R interact with Bcl-2 family members in β-cells is poorly understood. For simplicity, full signaling events downstream of IL-1R and TNFR are omitted, such as their cross-talk with each other, as well as the contribution of other relevant receptors such as that for interferon-γ.