APOPTOSIS AND ANTI-APOPTOTIC GENES OF THE BCL-2 FAMILY

Apoptosis, or programmed cell death, is art active process of self-des truction, 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 d evelopment, and tissue remodeling, and its purpose is to assure homeos tasis of cells and tissues. Apoptosis-defining morphological and bioch emical changes are now well documented Many physiological and non-phys iological factors have been described as inducers of apoptosis. Severa l genes affecting various steps in programmed cell death must be expre ssed to trigger apoptosis. For example, ced-3 and ced-4 in the nematod e C, elegans, and ICE, a gene found in mammals. In addition, the exist ence of genes suppressing apoptosis, like the human bcl-2 gene and a f amily of related bcl-2 genes was recently described. Several data deal ing with these family of anti-apoptotic genes and some of their mechan isms of action are now currently available. It is clear that bcl-2 pro tects 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), bar-alpha or bak can trig ger the opposite effect. it is known that bcl-2 can interact with othe r proteins. For example, bar, which can exist as a homodimer; is also able to form a heterodimer with bcl-2. A surexpression of bax in sever al cell lines allows to counteract the effect of bcl-2. R-ras p23 is a nother 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 re sults suggest that bcl-2 is a death repressor molecule functioning in an anti-oxydant pathway, but other recent data seem to claim the contr ary Recently, the demonstration was made that apoptosis may require th e activation of several classes of proteases. It seems now that bcl-2 has also a function of protease(s) inhibitor.