The two main pathways involved in apoptosis regulation. (a) The extrinsic pathway begins outside the cell through the activation of receptors on the cell surface by specific molecules known as pro-apoptotic ligands, including CD95L/FasL (receptor CD95/Fas). Once activated, the death domains of these receptors bind to the adapter protein Fas-associated death domain (FADD), resulting in the assembly of death-induced signaling complex (DISC) and recruitment and assembly of initiator caspases 8 and 10. The two caspases are stimulated and processed, releasing active enzyme molecules into the cytosol, where they activate caspases 3, 6, and 7, thereby converging on the intrinsic pathway. (b) The intrinsic (mitochondrial) pathway is initiated in response to cellular signals resulting from DNA damage, a defective cell cycle, detachment from the extracellular matrix, hypoxia, loss of cell survival factors, or other types of severe cell stress. This triggers activation of specific members of the pro-apoptotic Bcl-2 protein family involved in the promotion of apoptosis, Puma and Noxa, which in turn activate the pro-apoptotic proteins Bax or Bak. These two proteins move to the mitochondrial membrane and disrupt the anti-apoptotic function of the Bcl-2 family proteins, allowing for permeabilization of the mitochondrial membrane. Apaf-1, apoptotic protease activating factor 1; Bad, Bcl-2/Bcl-X
-associated death domain protein; Bak, Bcl-2 homologous antagonist-killer protein; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma-2; Bcl-X
, Bcl-2-related gene, long form; Bid, Bcl-2-interacting domain; Bim, Bcl-2-interacting mediator of cell death; Casp, caspase; Cyt c, cytochrome c; E2, 17β-estradiol; ER, estrogen receptor; ERE, estrogen-responsive element; FasL, Fas ligand; FLIP, FLICE-inhibitory protein; IAP, inhibitor of apoptosis; Noxa, phorbol-12-myristate-13-acetate-induced protein 1; Puma, p53-upregulated modulator of apoptosis.