Apoptosis and anti-apoptotic genes of the BCL-2 family

Apoptosis, or programmed cell death, is art active process of self-destruction, described a long time ago. However the understanding of the molecular pathways which regulate programmed cell death is more recent and far from complete. Apoptosis occurs during embryonic and foetal development, and tissue remodeling, and its purpose is to assure homeostasis of cells and tissues. Apoptosis-defining morphological and biochemical changes are now well documented. Many physiological and non-physiological factors have been described as inducers of apoptosis. Several genes affecting various steps in programmed cell death must be expressed to trigger apoptosis. For example, ced-3 and ced-4 in the nematode C, elegans, and ICE, a gene found in mammals. In addition, the existence of genes suppressing apoptosis, like the human bcl-2 gene and a family of related bcl-2 genes was recently described. Several data dealing with these family of anti-apoptotic genes and some of their mechanisms of action are now currently available. It is clear that bcl-2 protects many cell lines from induced apoptosis. Other proteins, like bcl-x(I), Al or mcl-1 have the same anti-apoptotic function, but several molecules of the same family, like bcl-x(S), bax-alpha or bak can trigger the opposite effect. it is known that bcl-2 can interact with other proteins. For example, Bax, which can exist as a homodimer; is also able to form a heterodimer with bcl-2. A surexpression of bax in several cell lines allows to counteract the effect of bcl-2. R-ras p23 is another example, among others, of a protein interacting with bcl-2, and this results in an interruption of the apoptotic signal transduction pathway when bcl-2 is overexpressed. Some other explanations allowing a more detailed analysis of the molecular mechanisms of apoptosis and anti-apoptosis are discussed in this short review. Many interesting results suggest that bcl-2 is a death repressor molecule functioning in an anti-oxydant pathway, but other recent data seem to claim the contrary. Recently, the demonstration was made that apoptosis may require the activation of several classes of proteases. It seems now that bcl-2 has also a function of protease(s) inhibitor.