Apoptosis death receptor activation

Death receptor activation. Several different ligands can induce apoptosis of neural cells including certain cytokines... 

Apoptosis can be induced by two pathways the extrinsic pathway starts with an activation of death receptors on the cell surface, which leads to the activation of caspases (Figure 5). Death receptors are a subgroup of the tumor necrosis factor (TNF) receptor family that have an intracellular death domain. Death receptors include CD95, TRAIL-Rl, and TRAIL-R2 (TNF-related apoptosis inducing ligand). The stimulated death receptors activate an adaptor protein FADD (Fas-associated death domain protein), which, in turn, activates the inactive form of caspase-8 (cysteine-aspartyl-specific proteases). Caspase-8 activates pro-caspase-3 and also the protein Bid (a member of the Bcl-2 family) that can stimulate and amplify the intrinsic pathway. 

There is also crosstalk between the two pathways above the mitochondria. The BH3-only protein BID is cleaved by caspase-8 and -10 which yields truncated BID (tBED), the active pro-apoptotic fragment of BID. Thereby, even in cells in which the direct apoptosis pathway which result from death receptor crosslinking is blocked, e.g. by high expression levels ofthex-linked IAP (XIAP), the activity of tBED on mitochondria can result in the activation of caspase-3 because the IAP-imposed block on full caspase-3 activation and caspase-9 activity at the apoptosome is released by Smac/ DIABLO. 

Topo inhibitors are found to be the most efficient inducers of apoptosis. The main pathways leading from topo-mediated DNA damage to cell death involve activation of caspases in the cytoplasm by pro-apoptotic molecules released from mitochondria. In some cells, the apoptotic response also involves the death receptor Fas (APO-1/CD95). The engagement of these apoptotic ef-... 

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

The death ligand and the death receptor There is, on the surface of the cytotoxic T cell, a ligand that binds to a specific receptor on the infected cell known as a death receptor. The ligand is known as the FAS ligand (or death ligand). This binding results, via activation of intracellular proteases, in stimulation of the caspase system, which initiates apoptosis (Figure 17.31). (See Chapter 20 for description of apoptosis.)... 

Figure 17.31 Death of virally infected host celis via the death receptor on the host cell to which is bound the death ligand on the surface of the cytotoxic T-cell. The interaction between the ligand and the receptor results in activation of caspases that induce apoptosis. The latter process results in disintegration of the cell, the results of which are apoptotic vesicles that are phagocytosed and destroyed by the macrophages.

When a cell is infected with a virus, the latter utilises the metabolic machinery within the host cell to generate viral proteins, RNA and DNA to produce more virus particles which then escape to infect other cells. The process is stopped by death of the host cells so that generation of new viruses is halted. The major mechanism that results in death of the host cell is apoptosis. The cells that are responsible for the death of the infected cells are either cytotoxic lymphocytes or natural killer cells. Death is caused either by release of toxic biochemicals and/or proteolytic enzymes or by binding to a death receptor, which is present on many cells. The entry of proteolytic enzymes or binding to the death receptor results in activation of initiator caspases. These activate effector caspases that cause damage to the cell which results in death due to apoptosis (Chapter 17 Figures 17.28, 29 and 30). 

Figure 14-8. Overview of pathways that regulate programmed cell death. Apoptosis may occur in response to signaling through either the extrinsic pathway or the intrinsic pathway. In each case, proteolytic cleavage activates an initiator caspase, caspase 8 or 9, either of which can cleave an effector caspase such as caspase 3. Apaf-1 is part of a large complex called the apoptosome that mediates the intrinsic pathway. Binding of an extracellular death ligand to its cell-surface receptor activates the extrinsic pathway.

The caspases that are involved in apoptosis may be further classified as either initiators or effectors. Induction of apoptosis via death receptors results in the activation of an initiator caspase. Caspases-8, -9, and -10 are initiators because they initiate the cascade of biochemical events that culminates in apoptosis. Caspases-3, -6, and -7 propagate this cascade (the so-called doomsday signal), thus functioning as effectors. Although there is some overlap, caspases-1, -4, -5, -11, -12, and -13 are involved in processing cytokines, thus influencing immunoregulation. The various caspases are listed in table 8.2. 

These proteins interact with the cofactor FADD in death-receptor-mediated apoptosis (see 15.4) and block its activating effect. 

Transactivation of proapoptotic genes is not the only way that p53 protein can activate the apoptotic program. There is evidence that variants of p53, which are independent of Bax protein and do not operate at the transcription level, can also result in apoptosis (see Haffner and Oren, 1995 Ko and Prives, 1996). Thus, a p53-regulated redistribution of the Fas death receptor from the cytosol to the cell membrane has been demonstrated (Beimet et al., 1998). Overall, these mechanisms are poorly understood. 

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

Figure 32-4 Sketch illustrating only a few of the many aspects of apoptosis in a mammalian cell. Emphasis here is on the death receptor pathways and cytochrome c-activated apoptosis. A third pathway is initiated by stress in endoplasmic reticulum membranes. In addition, attack by cytolytic T cells sometimes causes apoptosis by action of a granzyme on protein Bid or via a death receptor. Objects in scheme are not drawn to a single scale.

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