Extrinsic apoptosis pathway

Tun C, Guo W, Nguyen H, Yun B, Libby RT, Morrison RS, Garden GA (2007) Activation of the extrinsic caspase pathway in cultured cortical neurons requires p53-mediated down-regulation of the X-linked inhibitor of apoptosis protein to induce apoptosis. J Neurochem 102 1206-1219... 

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).

Beurel, E., and Jope, R. S. (2006). The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog. Neurobiol. 79, 173—189. 

Many elements of complex intrinsic and extrinsic signaling pathways leading to apoptosis have been identified. During apoptosis, a cascade of proteases termed caspases is involved with upstream signaling events and downstream executioner events. Caspases are cysteine-dependent, aspartate-specific proteases that contain highly conserved cysteine residues in their active sites and cleave substrates leaving C terminal Asp residues. Caspase-3 is one of the main effector molecules of the apoptotic process. It cleaves several target proteins and serves as one of the executioner caspases that implement apoptosis. Despite reports of caspase-independent apoptosis (Broker et al. 2005), caspase-3 has become the most widely accepted and most frequently measured apoptosis marker for HTS. 

Cohen, G. M. Caspases The executioners of apoptosis. Biochem. J. 326(Pt 1), 1-16,1997. Fulda, S., and Debatin, K. M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25, 4798-4811, 2006. 

N-terminus, a proline derivative in the third position, and an aromatic group at the fourth position. The studies mentioned above demonstrate Smac mimetics are effectors of both the extrinsic and the intrinsic apoptosis pathways. 

Similar interactions have been observed with the CDK inhibitor flavopiridol. Initial studies demonstrated that flavopiridol interacted synergistically with TNF to induce apoptosis in lung cancer cells. Subsequently, it was shown that co-administration of TRAIL with flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis in other tumor cell types (Senderowicz 1999 Rosato et al. 2004). Given evidence that flavopiridol acts at least in part to induce apoptosis in tumor cells via induction of mitochondrial injury, it seems plausible to propose that the potent tu-moricidal effects of a regimen combining TRAIL with flavopiridol, as in the case of HDACIs, stems from simultaneous activation of the intrinsic and extrinsic apoptotic pathways. 

Albeck, J.G., Burke, J.M., Aldridge, B.B. et al. 2008a. Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol Cell 30 11-25. 

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.

Li, Y., Song, Y.-H., Mohler, J., and Delafontaine, R 2006. ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression. Am. J. Physiol. 290 H2116-H2123. 

Caspase activation occurs as a late and common step in all cells undergoing apoptosis. Nevertheless, there are many initial pathways that can result in caspase activation. Probably, each distinct pathway is triggered by different apoptotic stimuli. In mammalian cells, the apoptotic response is usually mediated by the intrinsic and extrinsic pathways, depending on the origin of the death signal. The intrinsic pathway can further be divided into mitochondrial and ER stress pathways. 

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. 

There is evidence to suggest that both extrinsic and intrinsic pathways of caspase activation occur in the heart [36]. Some other signaling pathways have been suggested to mediate apoptosis in cardiomyocytes [37-39]. 

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