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Regulation of Apoptosis by TNF Superfamily Members

TNF superfamily members mediate both the intrinsic and extrinsic pathways of caspase activation. EDAR, Fas, DR3, TNF RI, TRAIL R1, TRAIL R2, NGF R, and DR6 initiate the extrinsic pathway via the recruitment of the adaptor proteins, FADD and TRADD, and pro-caspases. TNF family receptors that do not contain death domains, including 4-1BB, CD30, HVEM, LT beta R, TWEAK R, and RELT have also been shown to mediate apoptosis via indirect mechanisms such as inhibition of p38 or activation-induced cell death via NF-kappa B. TNF receptor superfamily-mediated apoptosis is not only critical for normal developmental processes but is also implicated in disease. For example, viruses encode cytokine responsive modifiers (CRMs) that act as TNF family decoy receptors and prevent apoptosis. Additionally, inhibition of TNF-mediated apoptosis, caused by the down-regulation of death receptors, up-regulation of decoy receptors, or altered intracellular signaling, is associated with cancer development. In addition to initiating apoptosis, several TNF family members, including CD27, BCMA, TACI, BAFF R, and OX40, inhibit apoptosis via activation of NF-kappa B and up-regulation of anti-apoptotic proteins. The TNF receptor family also includes six decoy receptors, DcR3, DcTRAIL R1, DcTRAIL R2, TRAIL R3, TRAIL R4, and OPG, which act to sequester TNF family ligands and prevent their normal physiological effects.