The Bcl-2 Protein Family

Abstract

Apoptosis is an increasingly well described, but still poorly understood, mechanism for killing metazoan cells (Kerr et al. 1972; Wyllie et al. 1980). It is fundamental to processes as diverse as tissue remodelling during embryogenesis, maintenance of tissue homeostasis in the adult and to both innate and cognate immunity (Ellis et al. 1991; Cohen et al. 1992; Raff 1992; Ameisen et al. 1994; Vaux et al. 1994; Strasser 1995b; Golstein 1997; Jacobson et al. 1997; Nagata 1997). Cells undergoing apoptosis exhibit characteristic changes in their appearance, notably plasma membrane blebbing and chromatin condensation (Kerr et al. 1972; Wyllie et al. 1980). Molecular indicators of apoptosis include internucleosomal DNA cleavage (Wyllie 1980), proteolysis of vital cellular substrates (Casciola-Rosen et al. 1996), externalisation of phosphatidyl-serine in the plasma membrane and expression of receptors that facilitate engulfment by phagocytes (Savill et al. 1993). Apoptosis can be caused by a broad range of physiological stimuli or experimentally applied stress conditions, and it appears that cells from all tissue types and from all multi-cellular organisms studied thus far possess this evolutionarily conserved death programme (Ellis et al. 1991; Raff 1992; Hengartner and Horvitz 1994c; Steller 1995; Vaux and Strasser 1996). Apoptosis can be induced via multiple independent pathways with distinct signalling intermediates. These routes all converge upon activation of latent cysteine proteases (caspases), leading to the proteolysis of vital cellular substrates and ultimately collapse of the cell (Vaux and Strasser 1996; Jacobson et al. 1997). Proteins of the Bd-2 family have been found to be key controllers of the cell death effector machinery.