Apoptosis: Molecular Regulation of Cell Death

Abstract

The field of apoptosis is unusual in several respects. Firstly, its general 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, the 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 three years. This review emphasises recent work on the molecular mechanisms of apoptosis and, in particular, on the intracellular interactions which control this process. This latter area is of crucial importance since dysfunction of the normal control machinery is likely to have serious pathological consequences, probably including oncogenesis, autoimmunity and degenerative disease. The genetic analysis of programmed cell death during the development of the nematode Caenorhabditis elegans has proved very useful in identifying important events in the cell death programme. Recently defined genetic connections between C. elegans cell death and mammalian apoptosis have emphasized the value of this system as a model for cell death in mammalian cells, which, inevitably, is more complex. The signals inducing apoptosis are very varied‐and the same signals can induce differentiation and proliferation in other situations. However, some pathways appear to be of particular significance in the control of cell death; recent analysis of the apoptosis induced through the cell‐surface Fas receptor has been especially important 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‐1β‐converting enzyme family of cysteine proteases and, second, those related to the proto‐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 considerable effort is being directed towards establishing the roles played by each member and the ways in which they interact to regulate apoptosis. Other genes with established roles in the regulation of proliferation and differentiation are also important in controlling apoptosis. Several of these are known proto‐oncogenes, e.g. c‐myc, or tumour suppressors, e.g. p.53, an observation which is consistent with the importance of 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 controlled cellular self‐destruction which ensues when the apoptosis programme has been engaged is also very important. The biochemical changes involved in inducing phagocytosis of the apoptotic cell, for e...

Reactive oxygen intermediate(s) (ROI): Common mediator(s) of poly(ADP‐ribose)polymerase (PARP) cleavage and apoptosis

“…Previous efforts were directed at the identification of the enzyme(s) responsible for the DNA fragmentation associated with apoptosis [2,9]. However, more recent results have shifted the emphasis from nuclear to cytoplasmic based components of the cell death process [13,14]. Early evidence suggesting the involvement of proteases during apoptosis arose from the realisation that CTLs and NK cells could kill using proteases.…”

Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression

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Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21Ras in IL-3-dependent hematopoietic cells

“…Although the promotion of cell proliferation has been believed to be a primary clue for the development of cancer (Anderson et al, 1992;Cantley et al, 1991;Schwab, 1990), the prevention of cell death is now recognized as an important step of oncogenesis (Hale et al, 1996;. For instance, an aberrant expression of Bcl-2 protein is known to protect cells from death rather than stimulating cell cycle transition (Korsmeyer, 1992).…”

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