Apoptosis and survival Caspase cascade
Caspase cascade
Caspases are the central components of the apoptotic response. The apoptotic caspasesare generally divided into two classes: the initiator caspases, which includecaspase-2, -8, -9 and -10 and the effector caspases, whichinclude caspases-3, -6 and -7. All caspases are produced in cellsas catalytically inactive zymogenes and must undergo proteolytic activation duringapoptosis. Activation of effector caspases is carried out by an initiator caspases. Once activated, the effector caspases are responsible for the proteolyticcleavage of a broad spectrum of cellular targets, which ultimately leads to cell death[1].
The apoptotic response is activated through either the intrinsic or theextrinsic pathway, depending on the origin of the death stimuli.
The intrinsic pathway is triggered in response to a wide range of deathstimulus that are generated from within the cell, such as oncogene activation and DNAdamage.
The intrinsic pathway is mediated by mitochondria: In response to apoptoticstimuli several proteins, such as cytochrome c, are released from theintermembrane space of mitochondria into the cytoplasm. Cytochrome c binds to andactivates the protein APAF1 in the cytoplasm that allows APAF1 to bind toATP/dATP and to form the apoptosome, which mediates activation of caspase-9,thereby triggering a cascade of caspase activation.
The extrinsic pathway is initiated by binding of an extracellular deathligand, such as FasL and TNF-alpha, to its cell-surface death receptor, such asFasR and TNFR. Adaptor protein FADD, TRADD, RIDDtransmit activating signal to effector caspases caspase-2, -8, and-10 [1].
Caspase-10 can function independently of caspase-8 in initiating Fas-and tumor necrosis factor-related apoptosis-inducing ligand-receptor-mediated apoptosis[2].
IGF-1 (insulin-like growth factor 1) exhibits strong anti-apoptotic activity.IGF-1 stimulates activation of AKT ( RAC serine/threonine-protein kinase)and AKT-induced inhibitory phosphorylation of caspase-9. Thereby IGF-1inhibits caspase-9 mediated apoptosis [3].
Activation of caspase-2 occurs in a complex that contains deathdomain-containing protein PIDD and the adaptor protein RAIDD [4].
The extrinsic pathway can crosstalk to the intrinsic pathway through thecaspase-8-mediated cleavage of BID (a BH3-ONLY member of the BCL2 FAMILY ofproteins), which then triggers the release of mitochondrial proteins.
The conserved IAP family of proteins can potently inhibit the enzymatic activity ofactive caspases. Caspases-3, -7 and -9 are subject to inhibitoryaction of XIAP (X-linked inhibitor of apoptosis), which is a member of IAP family[5].
Caspase-3 and caspase-6 are necessary for cleavage of a large number ofnuclear proteins essential for apoptosis-associated chromatin margination, DNAfragmentation, and nuclear collapse [6].
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