Apoptosis, inflammatory bowel disease and carcinogenesis: Molecular level (Part 3)
Notably, active caspase 8, depending on its amounts, can trigger one of two different signalling pathways. The first pathway of Fas-mediated apoptosis is activated by low amounts of caspase 8 and involves the cleavage of the proapop-totic Bid molecule, followed by the release of Cyt c from mitochondria into the cytoplasm, and subsequent death of the cell (Figure 1). The second pathway involves large amounts of caspase 8 that bypass mitochondria and activate other caspases such as caspase 3. The downstream smaller ‘effector’ caspases (caspases 3, 6 and 7) that are cleaved by active caspase 8, lack amino-terminal homoaffinity domains such as DDs, DEDs, or caspase recruitment domains but degrade a variety of cellular components including cytoskeletal proteins fodrin and gelsolin, nuclear lamins, and the inhibitor of caspase-activated DNase, which then permits activation of caspase-activated DNase to degrade DNA. This is your opportunity to purchase cialis online pharmacy http://purchasecialisonline.net taking full advantage of the nice options offered to you by most reliable pharmacies on the internet, with free delivery, express shipping and tons of other options you will appreciate.
Caspase 8 can also cleave the Bcl-2 homologue, Bid, to produce an active truncated Bid fragment that complexes with and inhibits Bcl-2 in the outer mitochondrial membrane to initiate the mitochondrial death sequence. Under normal conditions, Bcl-2 and Bcl-xL insert in the outer mitochondrial membrane and appear to help maintain mitochondrial integrity by allowing the export of hydrogen ions from the interm itochondrial space, or perhaps through their capacity to form an ion channel. In contrast, other Bcl-2 family proteins (Bid, Bad, Bak, Bax, Bim, and Noxa) complex with Bcl-2 or Bcl-xL and inhibit their action. Disruption of the outer mitochondrial membrane allows the leakage of two critical mediators of apoptosis. The first is Cyt c, which can complex with Apaf-1 and recruit caspase 9, forming the apop-tosome. In the presence of dATP this results in a conformational change in caspase 9 to render it active. The second mitochondrial factor is second mitochondria-derived activator of caspases, or direct inhibitors-of-apoptosis proteins (IAPs)-binding protein with low pI, which inactivates the IAP. This also results in activation of downstream effector caspases.
Figure 1) Apoptosis of mucosal T-cell by the Fas-Fas ligand (FasL) system and suppression of Fas-mediated apoptosis by interleukin (IL)-12. Normal lamina propria T (LPT) cells demonstrate an enhanced susceptibility to Fas-mediated cell death. Upon activation of Fas, the proteins Fas-associated death domain (FADD), cytotoxicity-dependent Apo-1-associatedprotein 3 (CAP3) andpro-caspase 8 are recruited to the death domain (DD) of the receptor, forming the death induced signaling complex (DISC). DISC signaling events result in the activation of caspase 8 which, in turn, either directly activates caspase 3 or induces cytochrome c (Cyt c) release from mitochondria. Cyt c in the cytoplasm binds to apoptotic protease activation factor(Apaf)-1, forming a complex that binds caspase 9 and causes its activation. Subsequently, activated caspase 9 activates other proteases, including caspase 3, and therefore causes cleavage of various substrates that subsequently lead to the death of the cell. However, in chronic intestinal inflammation, increased production ofIL-12 prevents Fas-mediated T-cell apoptosis, resulting to T-cell accumulation in the intestine. This mechanism of disease perpetuation can be successfully blocked by antibodies to IL-12 (7,13). ST AT4 Signal transducer and activator of transcription 4