Execution apoptosis pathway

The central dogma of apoptosis is that all the initiating pro-apoptotic stimuli converge on the mitochondrial compartment. Thus, although apoptosis can be initiated elsewhere, the execution phase of apoptosis induced by ionizing radiation needs mitochondria. How do DNA lesions trigger mitochondria Several metabolic pathways coimect mitochondria to the nucleus. 

Fig. 5. The execution phase of apoptosis. An apoptotic stimulus causes the release of cytochrome c from mitochondria. The first box contains the components required to activate caspase 9 card refers to the caspase-recruitment domain. Caspase 9 then activates caspase 3 (second box), which in turn activates caspase 6 (last box). The amino-acid sequences at the cleavage sites are shown. Caspases 3 and 6 also have a prodomain that is not present in the active protease in caspase 6 an additional cleavage removes a small portion of the middle of the protein. Various substrates of the caspases are shown, including the pathway by which caspase-activated deoxyribonuclease (CAD) is activated which in turn leads to DNA...

Granzyme B will cleave proteins at aspartate residues and will therefore activate pro-caspase 10 and can cleave factors like ICAD (inhibitor of caspase-activated DNase). However, Granzyme B can also directly activate caspase 3. In this way, the upstream signaling pathways are bypassed and there is direct induction of the execution phase of apoptosis. Recent findings indicate that this method of granzyme B cytotoxicity is critical as a control mechanism for T-cell expansion of type 2 helper T (Th2) cells. Moreover, findings indicate that neither death receptors nor caspases... 

Figure 1. Schematic of the apoplotic signaling pathways. The intrinsic apoptotic pathway consists of the mitochondrial pathway. The extrinsic pathway mediates apoptosis through activation of the death receptors, TNF-o/Fas receptors. Apoptosis is executed by activation of proteases, known as caspascs. ATP is essential for apoptosis. Bel-2 family proteins are apoptosis regulating proteins Bcl-2 inhibits while Bid, Bax, Bad facilitate apoptosis. An interaction between these two apoptotic pathways exists. See text for a more detailed explanation.

A unifying feature of all pro-apoptotic signal transduction pathways is their ability to relay a death stimulus to the caspases, enzymes responsible for the execution phase of apoptosis37. As noted previously, however, a caspase-independent mechanism of apoptosis has recently been proposed23. 

Cytoplasmic acidification has been shown to be an important feature in apoptotic cells and may be necessary for optimal activation of caspases and execution of the apoptotic pathway. In some systems, concurrent alkinalization of mitochondria is identified, suggesting PT-opening with diffusion of protons into the cytoplasm (18). On the other hand, in somatostatin-induced apoptosis of MCF-7 cells, a nonmitochondrial source of H+ was implicated in the development of caspase 8-independent cytoplasmic acidification and this acidification was shown to be necessary for the induction of mitochondrial alterations (39). SNARF-1 is the dye most commonly employed in cells to assess alterations in pH in the near-physiologic range (7.0-8.0). It can be excited by the 488 nm line of the argon ion laser and the... 

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