Caspases apoptosis initiators

BH3 domain) of the BH3-only proteins binds to other Bcl-2 family members thereby influencing their conformation. This interaction facilitates the release of cytochrome C and other mitochondrial proteins from the intermembrane space of mitochondria. Despite much effort the exact biochemical mechanism which governs this release is not yet fully understood. The release of cytochrome C facilitates the formation of the apoptosome, the second platform for apoptosis initiation besides the DISC. At the apoptosome which is also a multi-protein complex the initiator caspase-9 is activated. At this point the two pathways converge. 

Figure 20.35 Mechanisms by which external or internal stress leads to cell damage resulting in apoptosis. The stress leads to activation of initiator proteolytic enzymes (caspases) that initiate activation of effector caspases. These enzymes cause proteolytic damage to the cytoskeleton, plasma membrane and DNA. The activation of DNAases in the nucleus results in cleavage of DNA chains between histones that produces a specific pattern of DNA damage which, upon electrophoresis, gives a specific pattern of DNA fragments. The major endproduct of apoptosis are the apoptolic bodies which are removed by the phagocytes.

Tlie initiator caspases receive proapoptotic signals and initiate the activation of a caspase cascade. Tliey are activated by an interaction with a transmembrane receptor or by cytotoxic influences. A complex is thus formed known as the apoptosome (see 15.4). The effector caspases are activated by an upstream caspase via a cascade mechanism. They are the component that executes apoptosis, initiates degradation of central proteins and directs the cell to death. 

Signaling for apoptosis can be initiated from outside the cell (extrinsic or death receptor pathway) or from inside the cell (intrinsic or mitochondrial pathway) [31, 32]. In both pathways, signaling results in the activation of initiator caspases. Active initiator caspases then sequentially activate downstream effector caspases such as caspase -3, -6, and -7. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair... 

Similar to the MAP kinase cascades for protein phosphorylation, protease cascades exist, in which downstream proteases are activated by the action of upstream proteases (3). One of the most famous cascades is the caspase cascade that leads to apoptosis (Fig. 22) (11, 136). Caspases are Cys proteases that cleave the amide bond specifically after an Asp residue. Two types of caspases exist, initiator caspases (Caspase 2, 8, 9, 10) and effector caspases (Caspase 3, 6, 7). Both initiator and effector... 

Hetz, C.A., Hunn, M., Rojas, P., Torres, V., Le3don, L., and Quest, A.F. (2002). Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells onset of necrosis is associated with delayed ceramide increase. J Cell Sci 115, 4671-83. 

Mitochondria and Apoptosis The loss of mitochondrial integrity is a major route initiating apoptosis (see Chapter 18, section V). The intermembrane space contains procaspases —2, —3, and 9, which are proteolytic enzymes that are in the zymogen form (i.e., must be proteolytically cleaved to be active). It also contains apoptosis initiating factor (AIF) and caspase-activated DNAase (CAD). Cytochrome c, which is loosely bound to the outer mitochondrial membrane, may also enter the intermembrane space when the electrochemical potential gradient is lost. The release of cytochrome c and the other proteins into the cytosol initiates apoptosis. 

Stroke and, thus, contributes pivotally to significant losses in neurological functions. The major contributors of the apoptotic cell death are a family of cysteine proteases (caspases). They initiate apoptosis by cleaving key components of the neuronal infrastructure and activating the factors responsible for neural cell damage. 

Hay et al., 2004). It also has been shown to promote apoptosis through a non-Smad protein kinase (PK) C-dependent pathway (Hay et al, 2001). The non-Smad PKC-dependant path increases BAX/BCL-2 and increases the amount of cytochrome c released from the mitochondria therefore which activates cas-pase-9 and the other effector caspases to initiate osteoblast apoptosis (Hay et al, 2001). TGF-Pl exerts a negative regulation of BMP-2 at transcription (Sykaras and Opperman, 2003). 

Certain natural compounds possess anti-apoptotic effects. For example, ascorbic acid and a-tocopherol prevent apoptosis caused by serum withdrawal in HL-60 cells with the antioxidative effects (76). Caffeic acid inhibits ceramide-induced apoptosis in U937 cells through the inhibition of protein tyrosine kinase activity 17). Quercetin inhibits hydrogen peroxide-induced apoptosis via intervention in the activator protein 1 (AP-1) -mediated apoptotic pathway 18). Epigallocatechin-3-gallate and theaflavins inhibits arsenite-induced apoptosis through the decrease in phosphorylation of Erks and JNKs (79). Therefore, it is important to know whether these natural compounds show inhibitory effects on Trp-P-1-induced apoptosis. In this study, we demonstrated that Trp-P-1 induced caspase-8-initiated apoptosis in rat MNCs, and that certain food components inhibited Trp-P-l-induced apoptosis. 

Moreover, a recent study also revealed that ROS generation led to the activation of caspase-2 during p-carotene-induced apoptosis in the human leukemic T cell line Molt 4. The apoptosis progressed by simultaneous activation of caspase-8 and caspase-9, and a cross talk between these initiator caspases was mediated by the pro-apoptotic protein Bid. Inhibition of caspases 2, 8, 9, and 3 independently suppressed the caspase cascade. The cleavage of the anti-apoptotic protein BclXL was found to be another important event during P-carotene-induced apoptosis, suggesting the presence of an extensive feedback amplification loop in P-carotene-induced apoptosis (Prasad et al., 2006). 

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