: ALPS : cancer : caspase 8, caspase 10 : death-inducing complex : DISC : FADD : Fas-associated death domain protein : MAPK3/ERK1 : MAPK8/JNK : NF-κβ : peripheral tolerance : T cells, T-cells :
The adapter molecule FADD recruits caspase-8 to the activated receptor, and the resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation, which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases).
The protein encoded by the FAS gene is a member of the TNF-receptor superfamily. The TNF-receptors contain a death domain and play a central role in the physiological regulation of programmed cell death (apoptosis). The interaction of TNF-receptor and ligand causes the formation of a death-inducing signaling complex that includes the adapter molecule, Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the FADD complex triggers a downstream caspase cascade, leading to apoptosis.
TNF-R activates NF-κβ, MAPK3/ERK1, and MAPK8/JNK. It is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. At least eight alternatively spliced transcript variants, encoding seven distinct isoforms, have been described and the isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.
FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. TNF-Rs are implicated in the pathogenesis of immune system diseases and various cancers (T-cell ALL, multiple myeloma, lung cancer, malignant melanoma, bladder cancer, esophageal cancer, Ewing's sarcoma, etc).
FAS mutations are found in 83% of cases of ALPS (the autoimmune lymphoproliferative syndrome), an autoimmune condition in which lymphocytes fail to undergo apoptosis on schedule. The FAS gene is located on chromosome 10q24.1, and is member 6 of the tumor necrosis factor receptor superfamily.
: ALPS סּ apoptosis ф autoimmunity : cancer : caspase 8, caspase 10 סּ caspases : death-inducing complex סּ death receptor : DISC : FADD : Fas-associated death domain protein ¤ malignant transformation : MAPK3/ERK1 : MAPK8/JNK : NF-κβ : peripheral tolerance סּ receptor proteins : T cells, T-cells ф T cells :
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