APOPTOSIS - MOLECULAR REGULATION OF CELL-DEATH

The field of apoptosis is unusual in several respects. Firstly, its ge neral importance has been widely recognised only in the past few years and its surprising significance is still being evaluated in a number of areas of biology, Secondly, although apoptosis is now accepted as a critical element in the repertoire of potential cellular responses, t he picture of the intra-cellular processes involved is probably still incomplete, not just in its details, but also in the basic outline of the process as a whole. It is therefore a very interesting and active area at present and is likely to progress rapidly in the next two or t hree years. This review emphasises recent work on the molecular mechan isms of apoptosis and, in particular, on the intracellular interaction s which control this process. This latter area is of crucial importanc e since dysfunction of the normal control machinery is likely to have serious pathological consequences, probably including oncogenesis, aut oimmunity and degenerative disease. The genetic analysis of programmed cell death during the development of the nematode Caenorhabditis eleg ans has proved very useful in identifying important events in the cell death programme. Recently defined genetic connections between C. eleg ans cell death and mammalian apoptosis have emphasised the value of th is system as a model for cell death in mammalian cells, which, inevita bly, is more complex. The signals inducing apoptosis are very varied-a nd the same signals can induce differentiation and proliferation in ot her situations. However, some pathways appear to be of particular sign ificance in the control of cell death; recent analysis of the apoptosi s induced through the cell-surface Fas receptor has been especially im portant for immunology. Two gene families are dealt with in particular detail because of their likely importance in apoptosis control. These are, first, the genes encoding the interleukin-1 beta-converting enzy me family of cysteine proteases and, second, those related to the prot o-oncogene bcl-2. Both of these families are homologous to cell death genes in C. elegans. In mammalian cells the number of members of both families which have been identified is growing rapidly and considerabl e effort is being directed towards establishing the roles played by ea ch member and the ways in which they interact to regulate apoptosis. O ther genes with established roles in the regulation of proliferation a nd differentiation are also important in controlling apoptosis. Severa l of these are known proto-oncogenes, e.g. c-myc, or tumour suppres so rs, e.g. p53, an observation which is consistent with the importance o f defective apoptosis in the development of cancer. Viral manipulation of the apoptosis of host cells frequently involves interactions with these cellular proteins. Finally, the biochemistry of the closely cont rolled cellular self-destruction which ensues when the apoptosis progr amme has been engaged is also very important. The biochemical changes involved in inducing phagocytosis of the apoptotic cell, for example, allow the process to be neatly integrated within the tissues, under ph ysiological conditions. Molecular defects in this area too may have im portant pathological consequences.