Figure 1. Diagrammatic representation of the two pathways leading to apoptosis induction.

The “Bcl-2 family regulated” apoptotic pathway is initiated by cytotoxic stimuli, including DNA damaging agents and cytokine withdrawal, which perturb the balance between pro-survival and pro-apoptotic Bcl-2 family proteins within the cell, leading to activation of the downstream caspase cascade and ultimately apoptosis. The Bcl-2 family of proteins consists of the pro-apoptotic BH3-only proteins (including Bim, Bad, tBid, Hrk, Bmf, Bik, Puma and Noxa), the pro-survival Bcl-2 proteins (including Bcl-2, Bcl-x_L, Bcl-w, Mcl-1, A1 and Boo/Diva) and the pro-apoptotic executioner proteins (Bax, Bak and possibly also Bok). Signaling via the intrinsic pathway leads to the activation of the BH3-only proteins, by either transcriptional or post-translational mechanisms, allowing the BH3-only proteins to engage the Bcl-2 pro-survival proteins, thereby releasing Bax and Bak to induce mitochondrial outer membrane permeabilization (MOMP). The subsequent release of cytochrome c from the mitochondrial outer membrane, together with Apaf-1 and dATP, forms the apoptosome leading to the activation of the initiator caspase, caspase-9 and the activation of downstream activator caspases-3, -6, -7, which proteolyze hundreds of cellular proteins and result in the destruction of the cell. The “death receptor” pathway is initiated by the engagement of death receptors at the cell membrane that signal via the adaptor protein FADD to activate the initiator caspase, caspase-8, leading to activation of the effector caspases, caspases-3, -6 and -7 and apoptosis induction. The “death receptor” pathway can engage the “Bcl-2 family regulated” pathway through caspase-8 mediated cleavage and activation of the BH3-only protein Bid to tBid, which can then bind and sequester the Bcl-2 pro-survival proteins and/or directly activate Bax/Bak.