The Caspases System 1221 Caspase Activation

Apoptosis or program cell death was first introduced by Kerr, Wyllie, and Currie in 1972 as one of the homeostatic mechanism events that occur during many physiological processes such as cell proliferation, differentiation, and inflammatory response. The central component of this pathway is a family of aspartic acid-directed cysteine protease called caspases (CP, cysteinyl aspartate-specific proteinase). Until now, 14 caspases have been introduced in the human apoptotic pathway. At first, they are expressed as inactive form or proenzyme (pCP); after processing they are converted into active caspase form (aCP) [12] . The process of caspase activation starts with the removal of the inhibitory factor or binding of the cofactors either by a protease or by autocatalysis. During proteolysis, the prodomain part is cleaved and the association of the large and small subunits to form a heterodimer follows resulting into caspase activation. Caspases play a crucial role in cells that are destined for programmed death. Most of the caspases are present in cytoplasm; however, some can be found at the Golgi system (CP12) and in the mitochondria (CP2, CP3, and CP9) [13].

There are three different apoptosis pathways; each has a different caspase as an initiator: CP8 for type I or receptor-mediated apoptosis, CP9 for type II or mito-chondrial-mediated apoptosis, and CP12 for type III or endoplasmic reticulum-mediated apoptosis [14]. Receptor-mediated apoptosis is triggered by attaching the members of the death receptor superfamily such as CD95 (FAS) or tumor necrosis factor (TNF) superfamily to its corresponding ligand. This complex induces a FADD (Fas-associated death domain protein) in the cytoplasm to activate procas-pase-8. Activated caspase-8 induces procaspase-3, leading to production of cas-pase-3 and apoptotic substrate. The mitochondrial pathway occurs mostly in response to internal insult such as DNA damage and p53 activation. Pro- and anti-apoptotic members of the Bcl-2 family compete to regulate cytochrome c by a mechanism that has not been yet identified. Cytochrome c release into cytosol is followed by its association with Apaf-1 and then procaspase-9 to form the apopto-some [15]. Endoplasmic reticulum-mediated pathway is a novel caspase activation pathway which CP12 functions as the initiator caspase following endoplasmic reticulum stress [16].

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