Apoptosis is a form of programmed cell death that occurs under numerous developmental and physiological conditions in order to eliminate unwanted or damaged cells from organisms. The activation of apoptosis has important implications in a variety of diseases, including cancer, AIDS, and autoimmune diseases. 1) We are studying the catabolic effectors that carry out the apoptotic process and degrade DNA, RNA, and protein during programmed death or apoptosis. We have identified and characterized one nuclease, cyclophilin, as well as several other candidate enzymes which are now being purified. We have also shown that 28S ribosomal RNA is specifically degraded during apoptosis. This appears to be activated via the degradation of the ribosomal P3 protein. 2) Apoptosis is activated by many different signals operating through a diverse array of signal transduction pathways. Thus we have sought to define common activation pathways for apoptosis that are independent of both the apoptotic signal and cell type. We have shown that cell shrinkage must occur for the subsequent DNA fragmentation. These findings have directed our efforts to understand how cells regulate their volume and what ion fluxes occur during apoptosis. This is likely to be important in further deciphering mechanisms of apoptosis. 3) A third effort has been in the area of genetic approaches to define components of the cell death pathway. Somatic cell fusion studies show that the apoptotic phenotype is recessive and now developed a powerful selection screen using expression cloning to identify novel repressors of apoptosis. We are also identifying more genetically tractable systems to study apoptosis and now have data that indicates that apoptosis occurs in yeast. 4) We have also been deciphering the interplay between inhibition of cell growth and induction of apoptosis.
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