Ubiquitous over-expression of human X-linked inhibitor apoptosis (XIAP) in a transgenic mouse and implications for tumorigenesis

Abstract

The suppression of programmed cell death is an essential alteration in the transformation from normal to neoplastic growth. The X-linked inhibitor of apoptosis (XIAP) is a potent suppressor of apoptosis. It is a member of the Inhibitor of Apoptosis (IAP) family and functions by inhibiting caspases 3, 7 and 9 critical proteases in the process of programmed cell death. XIAP expression levels are frequently elevated in cancer cell lines and tumors, yet the link between XIAP expression and tumorigenesis has not been demonstrated experimentally. The objective of this project is to determine whether XIAP over-expression predisposes mice to cancer. A XIAP transgenic mouse model has been created with expression of the transgene driven by the ubiquitin C promoter. The UbiC-6-myc XIAP transgenics demonstrate ubiquitous over-expression of the human homolog of XIAP. Transgene over-expression was detected by western blot in all tissues tested including brain, retina, thymus, lung, heart, liver, kidney, pancreas, and spleen. The mice develop normally and show no unusual phenotype. Homozygous mice have been bred that show a further two-fold over-expression relative to their heterozygous littermates. Suppression of apoptosis has been documented in in vitro studies of mouse embryo fibroblasts and hepatocyte cultures. Transgenic XIAP provides protection against injury-induced apoptosis in vivo in a high dose streptozotocin induced pancreatic beta cell damage model in adult mice. The mice have been bred with an inducible c-myc oncogene transgenic strain that expresses c-myc in the beta cells of the islets of Langerhans when activated by tamoxifen (obtained from Dr. Gerard Evan). The myc/XIAP double transgenics responded in the same manner as the single c-myc transgenics and the beta cells underwent apoptosis. These results suggest a model where XIAP suppresses injury or stress induced apoptosis but is unable to block genetically pre-determined or oncogene-activated apoptosis.