Serial killers: ordering caspase activation events in apoptosis

Abstract

Caspases participate in the molecular control of apoptosis in several guises; as triggers of the death machinery, as regulatory elements within it, and ultimately as a subset of the effector elements of the machinery itself. The mammalian caspase family is steadily growing and currently contains 14 members. At present, it is unclear whether all of these proteases participate in apoptosis. Thus, current research in this area is focused upon establishing the repertoire and order of caspase activation events that occur during the signalling and demolition phases of cell death. Evidence is accumulating to suggest that proximal caspase activation events are typically initiated by molecules that promote caspase aggregation. As expected, distal caspase activation events are likely to be controlled by caspases activated earlier in the cascade. However, recent data has cast doubt upon the functional demarcation of caspases into signalling (upstream) and effector (downstream) roles based upon their prodomain lengths. In particular, caspase-3 may perform an important role in propagating the caspase cascade, in addition to its role as an effector caspase within the death programme. Here, we discuss the apoptosis-associated caspase cascade and the hierarchy of caspase activation events within it.

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

“…Thus, the increase in caspase activity in cells with XIAP downregulation or Smac overexpression initiated a feedback amplification loop acting back on the mitochondria to trigger further mitochondrial perturbations. Caspase-3 may contribute to this mitochondrial amplification loop by cleaving Bid, caspase-8 and/or caspase-2 (Slee et al, 1999(Slee et al, , 2000Sohn et al, 2005). Caspase-2 may also act upstream of mitochondria upon g-irradiation, as suggested by our data showing that the caspase-2 inhibitor zVDVAD.fmk reduced loss of mitochondrial membrane potential upon g-irradiation in the corresponding control cell lines, that is, cells infected with nonsense shRNA or empty vector.…”

“…Radiosensitization of pancreatic cancer S Giagkousiklidis et al activation of the initiator caspases-8 and -2 in a positive feedback loop (Slee et al, 1999(Slee et al, , 2000Sohn et al, 2005).…”

Is caspase inhibition a valid therapeutic strategy in cryopreservation of ovarian tissue?

“…So far, 14 members of the caspase family are known, and they can roughly be classified as initiator and executioner caspases according to their function [24][25][26]. Caspase-3, which can be activated by the initiator caspase-8 and caspase-9, as well as by the serine protease granzyme B, is a wellcharacterized typical executioner caspase involved in many proteolytic processes in apoptotic cells [25,26]. In particular, caspase-3 mediates the cleavage of proteins that are essential for cell stability, DNA repair and activation of Dnases [27][28][29].…”

Nonsense-mediated mRNA decay among human caspases: the caspase-2S putative protein is encoded by an extremely short-lived mRNA

“…1 Several human genes encoding caspases can undergo alternative mRNA splicing, which may lead to the production of shorter proteins. 2 Caspase-2 can function as both an initiator 3 and an effector 4 caspase, depending on the death stimulus and the cell type. The 12 exon-containing CASP-2 gene has been originally described to encode two isoforms with opposite roles in apoptosis.…”