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Boster Pathways-> Immunology and Inflammation
Cellular Apoptosis
an Overview of Cellular Apoptosis
When cells receive mixed signals for growth,they usually die e.g when the developmental programme requires cell division but external growth signals are lacking,or when a growth related gene like c-myc is highly expressed but the cellular environment has insufficient nutrient content,or a xenobiotic is present,the cell dies by a process termed apoptosis
The caspase cascade pathway plays a key role in several neurodegenerative disorders, including Parkinson’s disease, Alzheimer’s disease, tumorigenesis, and autoimmune disorders.
History of CELLULAR APOPTOSIS
Apoptosis was first described by a German Scientist Carl Vogt in 1842.later in 1885,an anatomist called Walther Flemming delivered a more precise descroption of the process of programmed cell death.in the next century I.e in the year 1965,while studying using electron microscopy,John Kerr at the university of queensland was able to distinguish apoptosis from traumatic cell death.
It is important to distinguish apoptosis from the major form of cell death,necrosis.to begin with,at the cell level,apoptosis produce little or no inflammation ,since shrunken portions of the cell are engulfed by the neighbouring cells,especially macrophages ,rather than being released into the extracellular fluid.in contrast,in necrosis,celluar content are released into the extracellular fluid and thus have an irritant effect on the nearby cells causing inflammation.
Cytochrome c is a central figure in the activation of the apoptotic intrinsic pathway.thereby activating the caspase cascade through the interaction with APAF-1 . Recents studies have revealed that is direct inhibitor of APAF-1 a a cytosolic cytochrome c target.caspase 9 proteolytically active caspase3. Smac/DIABLO are also released from the mitochondria along with cytochrome c during apoptosis.
Mechanism of action for Cellular Apoptosis
Endoplasmic reticulum stress leads to the CA ions mediated activation of caspase 12.
Fas and TNFR activate caspae 8 and 10.anti apoptotic members of the BcL-2 family fails to protect the cells from CH 1,SKW6.4 and SW480,all of which are lymphocyte lineages except the latter which is a colon adenocarcinoma lineage.caspase 8 catalyzes the cleavage of the pro-apoptotic BH-3 only protein Bid into its translated form,tBid.
In the case of TNFR 1,FADD recruitment requires prior binding of TRADD,FADD in turn recruits pro-caspase 2 through the recruitment of the death-inducing signaling complex.it also activates caspases through inhibiting signalling via NF-KappaB,which induces the expression IAP an inhibitor of caspases 3,7 and 9.
Apart from PARP,DNA-dependent protein kinase,PAK 1,GDIDH,lamin-A,B1,B2 are also cleaved thus inducing apoptosis.
Caspase 3 clevea ICAD; an inhibitor of CAD to free CAD to cause DNA fragmentation.
Granzyme B belong to a family of serine proreases expressed in the granules of CTL,NKs and perforin.they activates caspases and DNA fragmentation as well as some characteristics of necrosis e.g outer membrane degradation.granzyme B can enter the cytoplasm in the absence of perforin,but additon of perforin results in translocation of granzyme B into the nucleus and iitiation of apoptosis.once in the nucleus,it induces DNA fragmentation, may be by activating an endonuclease and cleaves PARP,producing a 64kd degradation product instead of the 85kd fragment produced by caspase cleavage of PARP.granzyme B can activate a number of caspases e,g caspase 3.