Figure 1.

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.

Yurube et al. Arthritis Research & Therapy 2014 16:R31   doi:10.1186/ar4460
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