Death receptor pathway

Figure 10.5 The death receptor pathway for DNA damage. Reprinted with permission from Hengartner, 2000. Copyright (2000) Macmillan Magazines Limited.

Ca2+ activation of gene expression. The MAP kinases (c-fos, c-myc, and c-jun) are activated as is also the Fas death receptor pathway. 

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.

Extrinsic (Death Receptor) Pathway of Caspase Activation. 5... 

Signaling for apoptosis can be initiated from outside the cell (extrinsic or death receptor pathway) or from inside the cell (intrinsic or mitochondrial pathway) [31, 32]. In both pathways, signaling results in the activation of initiator caspases. Active initiator caspases then sequentially activate downstream effector caspases such as caspase -3, -6, and -7. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair... 

Extrinsic (death receptor) pathway of caspase activation during apoptosis involves the binding of death ligands to cell surface receptors (e.g., Fas/ CD95/Apo-l or TNF receptor), recruitment of adaptor molecules Fas-associated death domain (FADD) or TNF receptor-associated death domain (TRADD) to the cytosolic end of the receptor, and formation of the death-inducing signaling complex (DISC) at the plasma membrane. DISC recruits and activates the initiator caspases, caspase-8 or -10. 

The mechanisms of apoptosis are highly complex and sophisticated, involving an energy-dependent cascade of molecular events (Figure 16.11). There are two main apoptotic pathways the extrinsic or death receptor pathway and the intrinsic or... 

Mitochondria are also susceptible to apoptotic pathways, mediated through members of (a) Bcl-2 family (Bid, Bad, and Bax), (b) death receptor pathway, and... 

Mechanisms underlying SM-induced apoptosis have been carefully explored using primary cultures of human keratinocytes. Treatment of keratinocytes with 100-300 pM SM resulted in activation of both caspase 8, which initiates the Fas-dependent death receptor pathway, and caspase 9,... 

The two main pathways of apoptosis, the death receptor pathway and the mitochondrial pathway, differ in the mechanism of activation of the initiator caspase but use the same effector caspase at least partially. 

Numerous experimental results have demonstrated that caspase-8 is the main caspase in the TNF family death receptor pathway (Fig. 1) whereas caspase-9 is the principal caspase of the mitochondrial pathway (Fig. 2) [17,18]. However, not all caspases are directly involved in apoptosis. The primary role of some caspases, including caspase-1, is the activation of pro-inflammatory cytokines. The inhibition of these proteases could thus be useful in controlling numerous diseases. The peptide drug VX-740, for instance, is a selective and reversible caspase-1 inhibitor that is intended to treat arthritis and other inflammatory diseases... 

Fig. 18.14. The death receptor pathway to apoptosis. The ligand (usually a cell surface protein on another cell) binds to the death receptor, which makes a scaffold for autocatalytic activation of caspase 8. Active caspase 8 directly cleaves apoptotic execution caspases. However, the pathway also activates Bid, which acts on mitochondrial membrane integrity.

Currently, all accumulating evidence indicate that asbestos is directly genotoxic by inducing DNA strand breaks by mechanisms that may include the generation of reactive oxygen and nitrogen species (catalyzed by iron), alteration in the mitochondrial function, and activation of death receptor pathway. Asbestos activates DNA repair enzymes such as, apurinic endonuclease and poly(ADP-ribose) polymerase (Upad-hyay and Kamp 2003). 

Srinivasula SM, Datta P, Fan XJ. Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J Biol Chem 2000 275 36152-36157. 

Insinga A, Monestiroli S, Ronzoni S et al. (2005) Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11 71-76... 

Mechanisms underlying SM-induced apoptosis have been carefully explored using primary cultures of human keratinocytes. Treatment of keratinocytes with 100-300 pM SM resulted in activation of caspase 8, which initiates the Fas-dependent death receptor pathway, and caspase 9, which initiates the mitochondrial apoptotic pathway (Rosenthal et al., 2003). Fas and Fas ligand were upregulated in a concentration-dependent manner by SM leading to activation of caspase 3, the central executioner protease. Transfection of immortalized keratinocytes with a dominant-negative Fas-activated death domain resulted in a blunted caspase response to SM. Micro vesication and tissue injury produced in vivo by SM exposure of transfected cells after grafting onto athymic nude mice was also reduced by this treatment. 

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