Dissecting the pathways to death

This report summarizes recent findings in the field of basic and translatio nal apoptosis research which were presented at the 1st Conference on 'Mecha nisms of Cell Death and Disease: Advances in Therapeutic Intervention' orga nized by the European School of Hematology and the University of Texas MD A nderson Cancer Center, 13-17 May, in Dublin, Ireland, and puts them in the context of the literature. Recent discoveries have significantly advanced t he understanding of biochemical and genetic requirements of distinct apopto sis pathways (ie mitochondrial, death-receptor and endoplasmic reticulum-me diated apoptosis) and their dysregulation in disease. Progress has been mad e especially in the elucidation of the mechanisms of action of the Bcl-2 fa mily members, in detail the formation of channels and their regulation in t he mitochondrial membranes, conformational changes in Bax and Bak, and cros stalk of death receptor-triggered apoptosis to the mitochondria by activati on of Bax via Bid. In addition, novel insights have been gained about the r egulation of caspases and novel caspase signaling pathways, such as activat ion of caspase-12 by the endoplasmic reticulum stress response. Therapeutic applications of apoptosis manipulation include (1) the inhibition of caspa ses in acute and chronic neurodegenerative diseases, ie stroke, Alzheimer's or Huntington's disease by drugs and (2) sensitization of cancer cells for drug/radiation-induced apoptosis by modulation of survival signals and vir al transfer of apoptosis promoting genes.