Intracellular death signals

In the literature, most dmg-induced apoptosis is well known to require intracellular hyper-production of reactive oxygen species and several antioxidants inhibit apoptotic cell death. While it is clear that peroxidation reactions induce apoptosis, the precise molecular mechanism of how reactive oxygen species convey death-signals is unknown. 

Other molecules are known to bind the intracellular portion of CD95 and regulate both positively or negatively the cell death signal. EAP-1 is a protein tyrosine phosphatase, which is highly expressed in CD95-resistant... 

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).

There are two distinct types of TNF receptors, TNF-R1 (CD120a or P55) and TNF-R2 (CD120b or P75). They are implicated in inflammatory processes and both belong to the TNF receptor superfamily. TNF receptors are transmembrane proteins with intracellular domains that lack intrinsic enzymatic activity, and consequently, they require cytoplasmic proteins that help initiate the receptor-induced signaling pathways. TNF-R1 possesses an intracellular death domain and TNF-R2 interacts with molecules of the TNF receptor-associated factor 2 family (TRAF). 

In the absence of a death signal, most of the pro- and anti-apoptotic members are located in separate subcellular compartments. Anti-apoptotic proteins are inserted in intracellular membranes, mainly the mitochondrial membrane, while some proapoptotic members are located in the cytoplasm or cytoskeleton in an inactive form. They are activated and translocated by apoptotic stimuli to their place of action to perform their functions (Gross et al., 1999). 

Mitochondria play a critical role in the control of cell death, because they provide a major intracellular apoptotic signal, cytochrome c.2 There are several, probably interrelated, ways in which mitochondria shed cytochrome c.25 Early in apoptotic cells, mitochondria undergo a permeability change that disrupts electron transport. This situation is charac-... 

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