The process of apoptosis, or programmed cell death, is of vital importance in human health and disease. Improved understanding of the regulation of apoptosis promises to lead to new therapeutic strategies for a number of diseases, including cancer, neurological degenerative conditions, and autoimmune dysfunction. Much of our current understanding of the regulation of apoptosis rests on a foundation established by studies in lower animals, including nematodes and insects. An example of the importance of studying cell death in lower animals is provided by the anti-apoptotic gene family called iap. The first iap genes were identified by the PI in baculoviruses, which are viruses of lepidopteran insects. Subsequently, iap homologs have been identified by sequence homology in the genomes of insects and higher animals, and there is evidence linking at least two iap genes to human diseases, namely cancer and spinal muscular atrophy. A novel sequence motif found only in IAP proteins, the BIR motif, is required for anti- death function, presumably through the ability of different BIR motifs to bind to a number of distinct pro-apoptotic proteins. However, the BIR motifs from different IAP proteins do not appear to be inter- changeable, and no detailed information is currently available on the sequence requirements for BIR function. The first two Specific Aims of this proposal address the molecular basis for IAP function, through detailed structure-function analyses and characterization of protein- protein interactions. The third Specific Aim utilizes an improved version of the functional assay used to identify the first iap genes. This improved assay will be used to screen both viral and cellular cDNA libraries for novel anti-apoptotic genes. The identification and characterization of new genes involved in the regulation of cell death will lead to improved understanding of apoptotic pathways in both insects and higher animals, and may also aid in understanding the function of IAP proteins.
