Fig. 1

Overview of extrinsic and intrinsic pathway of apoptosis. External way of apoptosis is mediated by death receptor (DR). DR is activated by binding to the corresponding ligand, and is activated by the initial caspase (caspase-8) and the effector caspase (caspase-3/7), which eventually leads to cell apoptosis. After FasL binds to DR Fas, DR4 or DR5, it causes local oligomerization and activation of Fas molecules. Fas recruits Fas-related death domain protein (FADD) in its cytoplasm activated Caspases-8 and triggerd apoptosis. Tumor necrosis factor (TNF) receptor 1 (TNFR1) ligation recruits early complexes composed of TNFR1-associated death domain protein (TRADD) and receptor-interacting serine/threonine protein kinase 1 (RIPK1) and recruits caspase-8 and makes dimerization. Active caspase-8 cleaves downstream targets to activate two different pathways: directly cleaves the executioner caspases, caspase-3 and caspase-7, or engages the cell-intrinsic pathway to amplify executor caspase by processing BH3-only protein BID activation. Caspases-3 and Caspases-7 also regulate the permeability of the outer membrane permeabilization and the release of cytochrome C. In the intrinsic pathway, multiple stimuli that cause cellular stress or damage usually activate one or more members of the BH3-only protein family. BH3-only protein activation exceeding a critical threshold overcomes the inhibitory effect of anti-apoptotic B-cell lymphoma-2 (BCL-2) family members and promotes the assembly of BAK-BAX oligomers in the outer mitochondrial membrane. Activated BH3 protein activates BCL-2 antagonist/killer (BAK) and BCL-2 associated X protein (BAX) to induce mitochondrial outer membrane permeability and cytochrome C release. Cytochrome C binds and oligomerizes apoptotic protease-activating factor 1 (APAF1), which recruits and activates caspase-9. Cytochrome C and APAF1 combine to form an apoptosome that drive the activation of caspase-9, which stimulates caspase-3 and -7, and then induces apoptosis