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Caspase Action: Control of caspase action is central for apoptotic cell death

Caspases are thought to be universal effectors of apoptotic cell death.  These enzymes are synthesized as dormant ‘prozymogens’ and, during apoptosis, they are activated through complex cascades of proteolytic activation.  These events ultimately mediate cell death by cleaving selected substrates, thereby reorganizing cellular physiology and promoting self-destruction.  Apoptosis can be prevented when caspase function is blocked, either mutation or by inhibitors (viral or man-made).  CED-3, a gene discovered in the nematode, represents a founding member of the pro-apoptotic caspase family.  Homologous counterparts in mammals (caspase 9) and flies (Dronc) and their conserved upstream regulators are schematized in the figure.  For example, CED-4, bears homology to vertebrate APAF-1 and Drosophila Dark.  These ‘adaptor’ proteins activate apical caspase function via a multimeric complex referred to as the ‘apoptosome’.  In flies and mammals, an emerging picture for apoptosis control is consistent with a 'gas and brake' model, whereby concurrent input from APAF-1/Dark adaptors, together with removal of IAP inhibition drives caspase activation to levels that exceed a threshold necessary for apoptosis.  From this viewpoint, the balance of opposing regulatory forces determines the status of apical caspase activity but the relative contribution from positive regulators (APAF-1/Ced-4/Dark) and negative regulators (the IAP family) can vary among different cell types and species.  For example, in the worm, mouse and fly, mutations in positive regulators cause global cell death defective phenotypes but this is not consistently true with respect to the negative regulators (IAPs).  Therefore, while underlying components are broadly conserved, the regulatory ‘linchpins’ in different cells and in different species can vary.