Apoptosis death receptor role

Mice that lack caspase-1, -11, or -12 do not have a significant decrease in viability and have no overt consequence on their development [57-59,69,72]. In contrast, caspase-3 and/or -9 ablation results in retarded developmental apoptosis and has a tremendous impact on animals viability and phenotype [61, 67]. Similarly, caspase-8 knockout mice die in utero and are characterized by impaired formation of cardiac muscle and marked abdominal congestion with reduction of the number of hematopoietic precursors [65], The size of the heart was reported to be almost normal, but the developing ventricular musculature was thin and sometimes similar to early mesenchyme. The trabeculae were thin and disorganized. Cultured fibroblasts from caspase-8 mice were resistant to death receptor-mediated apoptosis. These findings indicate that caspase-8 plays an important role in death induction by several receptors of Fas/TNF/NGF family. Similarly, Sakamaki et al. [66] described that protease-deficient caspase-8 mutant mice died in utero due to heart rupture which they believe was due to cardiomyocyte apoptosis. 

We have already alluded to the fact that the NGF-activated p75 4TR receptor is a potential death receptor, like other members of the TNF family of receptors. Evidence is now becoming available that NGF-dependent activation of p75 s can initiate ceU death and apoptosis, whereas NGF and neurotrophin-binding to TRKs (growth-factor tyrosine-kinase-type receptors) has the opposite effect and prevents cell death. Thus, early in development, endogenous NGF causes the death of neurons that express p75 4TR whereas cells that express TRK receptors are not affected and survive. Thus, the fate of developing neurons depends on the type of the receptor e3q>ressed.55 This points to the central role of programmed ceU death in the development of the nervous system.5 ... 

Recruitment of the initiator procaspases into a multiprotein complex results from a regulated series of protein-protein interactions mediated by interaction modules . Four types of interaction modules are involved in the activation of initiator caspases and thus play important roles in the initiation of apoptosis (review Weber and Vin-cenz, 2001). These domains have been named the death domain (DD),, the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the less characterized pyrin domain. The domains are found on several components of the apoptotic signaling pathways and mediate homotypic protein-protein interactions, i. e., a given module will interact only with a member of the same family and not with members of the other families. Since members of the same module are found on different proteins, these modules mediate the assembly of hetero-oligomeric protein complexes. As examples, DDs are found on death receptors and their cofactors, D EDs on cofactors and the initiator caspase-8, and CARDS on cofactors, caspase-2, and caspase-9. 

Apoptosis induced by death receptors can be controlled at several levels. Outside of the cell, the aggregation status of the ligand and the presence of soluble or membrane-bound decoy receptors have important regulatory roles. Anti-apoptotic intracellular proteins can block the apop-totic-signalling pathway or divert it into distinct responses. In addition, the overall sensitivity of a cell to apoptosis can be affected by engagement of receptors that do not themselves contain a death domain. The data presented below will exemplify some of these aspects. 

Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer J-L, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388 190-195 Ishiyama H, Ogino K, Hobara T (1995) Role of Kupffer cells in rat liver injury induced by diethyldithiocarbamate. Eur J Pharmacol 292 135-141 Itoh N, Nagata S (1993) A novel protein domain required for apoptosis. Mutational analysis of human fas antigen. J Biol Chem 268 10932-10937... 

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... 

In addition to its importance for inflammatory responses, NF-kB also plays a role in the regulation of cell homeostasis and apoptosis [62-64] and it was thus straightforward to assume a link between the known cytotoxic activity of STLs and their NF-kB inhibitory activity [3], It was demonstrated that helenalin indeed induces apoptosis and that it does so via a CD95 death receptor independent pathway and requires the activation of caspases [43], Further STLs for which quite detailed studies on pro-apoptotic activity and mechanism exist are the germacronolides parthenolide and costunolide (structures 32 and 52 in Fig. (9)) [44, 45]. 

Apoptosis (programmed cell death) is a genetically controlled cell suicide process that has an essential role for the maintenance of homeostasis and prevention of cancer and some other diseases substantially in all living cells [141], Apoptosis is an optional elimination method for irreversibly damaged cells. The two major pathways that initiate apoptosis are extrinsic (death receptor mediated) and intrinsic (mitochondrial mediated). In addition, mitogenic and stress-responsive pathways are involved in the regulation of apoptotic signaling [142],... 

APOPTOSIS, or programed cell death, plays an important role in the development of organisms and in the maintenance of homeostasis. The failure of apoptotic programs causes various diseases. So far, many genes regulating apoptosis have been identified and the molecular mechanism of apoptosis is being clarified. In this article, I will discuss cell death elicited through death receptors. 

Gene disruption experiments have revealed the physiological functions of individual caspases in vivo. (1) Caspase-3- and -9-deficient mice show embryonic lethal phenotypes with neuronal hyperplasia, indicating that caspase-3 and -9 play an important role in neuronal development. Moreover, their embryonic fibroblasts are resistant to staurosporine-, etoposide-, UV-, and dexamethasone-induced apoptosis but not to Fas-mediated apoptosis. (2) Caspase-8-null mice are embryonic lethal and established cells from these mice are resistant to cell death through death receptors including Fas, DR3, and TNFRI, whereas these cells are sensitive... 

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