Apoptosis is a naturally occurring process by which a cell is directed to Programmed Cell Death. Apoptosis is based on a genetic program that is an indispensable part of the development and function of an organism and is a regulated physiological process leading to cell death. In apoptosis pathways, signaling results in the activation of a family of Cysteine Proteases, named Caspases that act in a proteolytic cascade to dismantle and remove the dying cell,are central regulators of apoptosis.Initiator caspases (including 8, 9,10) are closely coupled to pro-apototic signals. Once activated, these caspases cleave and activate downstream effector caspases (3,6,7) which in turn cleave cytoskeletal and nuclear proteins and induce apoptosis. Cytochrome C released from damaged mitochondria is coupled to the activation of caspase 9.
Pro-apoptotic stimuli include the FasL, TNF, DNA damage. Fas and TNFR activate caspases 8 and 10; DNA damage leads to the activation of caspase 9. Anti-apoptotic ligands including growth factors and cytokines activate AKT and p90RSK, which inhibit Bad and prevent cytochrome C release. TNFR can also stimulate an anti-apoptotic pathway by inducing IAP, which directly inhibits caspases 3, 7 and 9.
Alternatively, apoptosis is inhibited via an adaptor protein complex which activates NF-kB and induces survival genes including IAP. The Bcl-2 family of proteins regulate apoptosis by controlling mitochondrial permeability and the release of cytochrome C. The anti-apoptotic proteins Bcl-2 and Bcl-xL reside in the outer mitochondrial wall and inhibit cytochrome C release. The pro- apoptotic Bcl-2 proteins Bad, Bid, Bax and Bim reside in the cytosol but translocate to mitochondria following death signaling, where they promote the release of cytochrome C. Bad translocates to mitochondria and forms a pro-apoptotic complex with Bcl-xL. This translocation is inhibited by survival factors that induce the phosphorylation of Bad, leading to its cytosolic sequestration. Bax and Bim translocate to mitochondria in response to death stimuli, including survival factor withdrawal. Bcl-xL, Bcl-2 and Bax apparently influence the voltage-dependent anion channel (VDAC), which can control cytochrome C release. p53, activated following DNA damage, induces the transcription of Bax. Released cytochrome C binds Apaf1 and forms an activation complex with caspase9.
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