"Where, O death, is thy sting?" A brief review of apoptosis biology

Abstract

Apoptosis was a term introduced in 1972 to distinguish a mode of cell death with characteristic morphology and apparently regulated, endogenously driven mechanisms. The effector processes responsible for apoptosis are now mostly well known, involving activation of caspases and Bcl2 family members in response to a wide variety of physiological and injury-induced signals. The factors that lead of the decision to activate apoptosis as opposed to adaptive responses to such signals (e.g. autophagy, cycle arrest, protein synthesis shutoff) are less well understood, but the intranuclear Promyelocytic Leukaemia Body (PML body) may create a local microenvironment in which the audit of DNA damage may occur, informed by the extent of the damage, the adequacy of its repair and other aspects of cell status.

Fig. 1

Diagrammatic representation of the interaction of BH3-only members of the BCl2 family with the bax/bak–BCl2/BCl_XL complexes on mitochondrial membranes, relative to a variety of injury stimuli

Fig. 2

Nucleus of a cell injured by IR 4 hours previously, showing the juxtaposition of IR induced foci (identified by an antibody to ATM, labelled red) with PML bodies (identified by an antibody to PML, labelled green). Courtesy of Dr. Brian Ferguson

Fig. 3

A variety of different potentially lethal stimuli, each recognised by a specific set of transcription factors and signalling molecules, initiate the adaptive reactions of cycle arrest, autophagy and protein synthesis shutoff. For reasons that are still poorly understood, these reactions can be over-ruled by cell death, apparently by an endogenously controlled mechanism

Fig. 4

Schematic diagram showing the relationship between AKT activation (survival stimulus) with adaptive reactions to oxygen and nutrient deprivation that lead to autophagy, cycle arrest and inhibition of the AKT/mTOR pathway that would otherwise have stimulated protein translation