Caspase cascade
The caspase cascade plays a vital role in the induction, transduction, amplification, and execution of apoptotic signals within the cell (Figure 2.6).
Click here to view a PDF of this image.Figure 2.6. The caspase cascade.
The caspases are a group of intracellular cysteine enzymes that — upon activation through the intrinsic and/or extrinsic pathways — destroy essential cellular proteins, leading to controlled cell death. There are 2 tiers of caspase activation during apoptosis. Initiator caspases (caspases 2, 8, 9, and 10) are activated through the apoptosis-signaling pathways and activate the effector caspases (caspases 3, 6, and 7) which, in an expanding cascade, carry out apoptosis.12,18 Caspase cascades are initiated through assembly of multiprotein complexes that trigger activation of the initiator caspases, which are then released and able to activate the downstream effector caspases.
Under normal conditions, caspase activity is held in check by c-FLIP proteins and the IAP protein family, of which at least 10 have been identified, including XIAP, cIAP1, cIAP2, ILP2, MLIAP, SURVIVIN, and BRUCE.12,23 IAPs are characterized by the presence of between 1 and 3 specific domains called baculoviral repeats (BIRs), which are directly involved in their caspase-inhibitory activity. While not directly involved in apoptotic signaling per se, some of these proteins prevent cell death by suppressing endogenous initiator and effector caspase activity (Figure 2.7). Emerging evidence also suggests that IAPs may play a role in modulating cell division.24 The IAPs SURVIVIN and c-IAP1 are overexpressed in several malignancies.24
Click here to view a PDF of this image. Figure 2.7. IAPs and caspase inhibition.
Adapted from Ashkenazi, 2002.1 Reproduced with permission from Nat Rev Cancer.