Programmed cell death' regulation:: Towards a more dynamic conception

Programmed cell death is essential for the development and maintenance of multicellular organisms and alterations in control of cell death/survival contribute to the pathogenesis of many human diseases. Cell death is ultimately executed by caspases, a family of cysteinil aspartate specific proteinases that cleave critical intracellular proteins and execute the apoptotic program. At least two major pathways for caspase activation have been identified: (1) the receptor-mediated pathway which involves members of the tumor necrosis factor (TNF) family of death receptors and (2) the mitochondrial-mediated pathway involving SIMP (soluble inter membrane mitochondrial proteins) released from the mitochondria. A formation of a multi protein complex which forms a template for efficient caspase processing is characteristic for each pathway respectively: the DISC (death inducing signaling complex) is formed by the death receptor and a set of cytosolic adaptor proteins (including procaspase) rapidly recruited to the membrane after ligand binding, and the apoptosome contains cytochrome c, Apaf-1 and procaspase 9. The function of these two complexes is modified at different levels by multiple inhibitory proteins: Flips (FADD-like ICE inhibitory proteins), IAPs (inhibitor of apoptosis protein) and the Bcl-2 family members. The role of other protein complexes formed at other locations within the cell, such as the nucleus that might have a role in cell death regulation will be also discussed.