Fig. (3) Curbing Bak/Bax pro-apoptotic function. The “direct” model proposes that the pro-survival proteins (Mcl-1, Bcl-2 and Bcl-xL shown) sequester “activator” BH3-only proteins (Bim, tBid and Puma) thereby preventing them from activating Bak and Bax. In response to cytotoxic stress, activator BH3-only proteins are displaced from the pro-survival proteins by the “sensitiser” BH3- only proteins (e.g. Noxa and Bad). Bim, tBid and Puma are potent inducers of cell death due to their ability to bind and activate Bak/Bax. The “indirect” model proposes that the pro-survival proteins protect a cell by binding and sequestering Bak and Bax rather than BH3-only proteins. During cell death the BH3-only proteins bind either promiscuously (Bim, tBid and Puma) or selectively (e.g. Noxa and Bad) to pro-survival proteins. Occupation of the pro-survival proteins is sufficient to liberate active Bak/Bax to kill the cell. In this scenario, Bim, tBid and Puma are potent inducers of cell death due to their ability to bind and inhibit all pro-survival proteins whereas the selective binders are relatively weak killers unless expressed in combination.