Like all apoptotic cell death, T cell receptor (TCR)-mediated death can bedivided into two phases: an inductive phase and an effector phase. The effector phase includes a sequence of steps that are common to apoptosis inmany cell types, which, if not interrupted, will lead to cell death. Theinduction phase, which often requires the expression of new genes, consistsof a set of signals that activate the effector phase. Outside the thymus,most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimesreferred to as activation-induced cell death (AICD)) is induced through thesurface antigen Fas pathway: activation through the TCR induces expressionof the Fas (CD95) ligand (FasL); the expression of FasL on either aneighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas,which then initiates a signal-transduction cascade, leading to apoptosis of the Fas-bearing cell. This commitment stage requires the activation of keydeath-inducing enzymes, termed caspases, which act by cleaving proteins thatare essential for cell survival and proliferation[, ]. However whathappens to FasL itself remains unknown. It is possible that it is cleavedfrom the effector cells and internalised into the target cells; it may bedownregulated in the effector cells; or it may be phagocytosed by the targetcells.Fas is also known to be essential in the death of hyperactivated peripheralCD4 cells: in the absence of Fas, mature peripheral T cells do not die, butthe activated cells continue to proliferate, producing cytokines that leadto grossly enlarged lymph nodes and spleen. Defects in the Fas-FasL systemare associated with various disease syndromes. Mice with non-functional Fasor FasL display characteristics of lymphoproliferative disorder, such as lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. Thesemice also secrete anti-DNA autoantibodies and rheumatoid factor [].FasL (also known as tumor necrosis factor ligand superfamily member 6) is a 40kDa type II membrane protein belonging to the tumour necrosisfactor (TNF) family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. It is expressed on activated lymphocytes, NK cells,platelets, certain immune-privileged cells and some tumour cells[, ]. The cell death-inducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL [].Human and mouse FasL induce apoptosis in cells expressing either mouse orhuman Fas with the same specificity. Although the amino acid sequence ofFasL is highly conserved between human and mouse, the similarity betweenhuman and murine Fas is much less pronounced. Greater conservation of theligand than the receptor is also observed in other members of the TNF family.By comparison with other TNF family members, FasL has a long N-terminal intracellular region rich in proline residues, which is known tobind to the SH3 domain. SH3 domains play important roles in mediating specificprotein-protein interactions, specifically in the cytoskeleton.
Prostate apoptosis response 4 (Par-4) induced apoptosis of selective prostate cancer cells PC-3, DU-145, and TSU-Pr and caused tumor regression by inhibition of NF-kappaB activity and cell membrane trafficking of Fas and FasL that leads to the activation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway []. It modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. It down-regulates the anti-apoptotic protein BCL2 via its interaction with WT1 []. Par-4 also regulates the amyloid precursor protein (APP) cleavage activity of BACE1 [].
This entry represents the death domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS [, ]. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity [].DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes [, ].
Like all apoptotic cell death, T cell receptor (TCR)-mediated death can bedivided into two phases: an inductive phase and an effector phase. The effector phase includes a sequence of steps that are common to apoptosis inmany cell types, which, if not interrupted, will lead to cell death. Theinduction phase, which often requires the expression of new genes, consistsof a set of signals that activate the effector phase. Outside the thymus,most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimesreferred to as activation-induced cell death (AICD)) is induced through thesurface antigen Fas pathway: activation through the TCR induces expressionof the Fas (CD95) ligand (FasL); the expression of FasL on either aneighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas,which then initiates a signal-transduction cascade, leading to apoptosis of the Fas-bearing cell. This commitment stage requires the activation of keydeath-inducing enzymes, termed caspases, which act by cleaving proteins that are essential for cell survival and proliferation[, ].Fas is also known to be essential in the death of hyperactivated peripheralCD4+ cells: in the absence of Fas, mature peripheral T cells do not die, butthe activated cells continue to proliferate, producing cytokines that leadto grossly enlarged lymph nodes and spleen. Fas belongs to the tumournecrosis factor receptor (TNFR) family of cysteine-rich type I membranereceptors; its ligand (FasL) is expressed on activated lymphocytes, NK cells,platelets, certain immune-privileged cells and some tumour cells [, ].Defects in the Fas-FasL system are associated with various disease syndromes.Mice with non-functional Fas or FasL display characteristics of lympho-proliferative disorder, such as lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. These mice also secrete anti-DNA autoantibodiesand rheumatoid factor [].
