Schematic illustration summarizing apoptotic signaling through the death receptor pathway and the mitochondrial pathway. The death receptor pathway is initiated by extrinsic signals such as the binding of death-inducing ligands (for example, Fas ligand (FasL)), to cell-surface receptors (for example, Fas). This complex cleaves the pro-form of initiator caspase-8, followed by direct or indirect (via the mitochondrial signaling loop) cleavage of the pro-form of effector caspase-3. The mitochondrial pathway is initiated by intrinsic signals (for example, DNA damage). DNA damage acetylates p53, which is deacetylated by the silent mating-type information regulation 2 homolog 1 (SIRT1). DNA damage phosphorylates p53 by dissociation of the complex of p53 and its negative regulators, murine double minutes 2 (Mdm2) and 4 (Mdm4). The p53 phosphorylation at serine 46 induces p53-regulated apoptosis-inducing protein 1 (p53AIP1) expression. p53AIP1 interacts with B-cell lymphoma 2 (Bcl-2). Imbalanced Bcl-2 family members (such as proapoptotic Bcl-2-associated X protein (Bax), Bcl-2-associated agonist of cell death (Bad), and BH3-interacting domain death agonist (Bid) and antiapoptotic Bcl-2), induce mitochondrial membrane permeabilization, cytochrome c release, and cleavage of the pro-form of initiator caspase-9 followed by caspase-3 cleavage, resulting in apoptosis.