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Caspases are a family of cysteine proteases that respond in succession when activated by apoptosis stimuli, leading to proteolysis, cell disassembly, and apoptosis. The caspase cascade can be triggered by stimuli from the cell surface or the mitochondria. Pro-apoptotic stimuli, such as TNF (Tumor Necrosis Factor), FasL (Fas Ligand), GRB (Growth Factor Receptor-Bound Protein), Granzyme-B, DNA damage, calcium channels, etc., are linked with initiator caspases (caspase 2, 8, 9, 10). When stimulated, initiator caspases cleave and trigger downstream executioner caspases (caspase 3, 6, 7) which further cleave other proteins, eventually resulting in cell death.
The caspase cascade pathway plays a key role in several neurodegenerative disorders, including Parkinson’s disease, Alzheimer’s disease, tumorigenesis, and autoimmune disorders.
In 1993,H Robert Horvitz and Junging Yuan found that the ced-3 gene was encoding the enzyme cysteine protease which has similar properties with the mammalian interleukin-beta converting E(ICE) which is now known as caspase 1.in 1996,the nomenclature of the CASPASE was decided and the caspase were to be named in theor order of idenification I.e caspase 1,2,3…
They are family of cysteine proteases that respond in succession when activated by apoptosis stimulus,leading to proteolysis,cell disassembly and apoptosis.
Caspase cascade can be triggered by stimuli from the cell surface or from the mitochondria. apoptotic stimuli is what governs the pathway leading to caspase activation.initiator casoases I.e caspases 8,9,10,12 are coupled to pro-apoptotic signals.
FasL,DNA damage,CA ions channels,Tumor Necrosis Factor and Gramzyme-B are the pro-apoptotic stimuli.
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.
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.