Apoptotic signal transduction: emerging pathways

Abstract

Apoptosis is a counterbalance to mechanisms of cell proliferation and is critically important in regulation of the immune system, development, and normal tissue homeostasis. Mammalian signal transduction pathways affecting apoptosis are more complex than their counterparts in the nematode Caenorhabditis elegans, a valuable model system that has provided powerful initial insights into key molecules regulating apoptosis. Despite this complexity, substantial progress has been made in recent years towards defining the nature and detail of signalling pathways bringing about apoptosis in mammalian cells. In particular, the identity and precise substrate specificities of a large family of caspase enzymes, implicated as critical components of the apoptotic machinery, have been defined. In addition, the mechanism by which the cell surface Fas receptor mediates induction of apoptosis, via activation of caspases, has recently been elucidated. A prominent role for mitochondria in cell death pathways has also recently emerged, a clear theme being that mitochondria can trigger degradative events by the release of apoptogenic proteins (e.g., cytochrome c) from the intermembrane space to the cytosol. This review focusses on recent progress in these areas and discusses integration of this knowledge in our overall understanding of the processes that control apoptosis.Key words: caspases, Fas receptor, mitochondria, cytochrome c, AIF.