The broad objective of this project is to use mutant strains of mice to dissect the genetic basis of hematopoietic malignancy and the role of proto-oncogenes and tumor suppressors in normal hematopoiesis. Transgenic lines with lymphoid-specific expression of nine oncogenes have been characterized, including four thought to influence programed cell death (apoptosis): myc, bcl-2, v-abl and cyclin D. Since perturbation of apoptosis is now recognized as central to tumorigenesis, in the next grant period the project will address five issues regarding the control of apoptosis and how it relates to lymphoma development. 1. Function and expression pattern of a novel survival gene, bcl-w. To clarify the biology of this bcl-2 homolog, bcl-w-deficient mice will be generated and a sensitive reporter gene introduced into the bcl-w locus to reveal its expression pattern throughout development. 2. Impact of Bcl-2 on cell cycle control. A clue to Bcl-2 function has emerged from the preliminary evidence that Bcl-2 promotes cell cycle exit and retards re-entry. T-cell populations from bcl-2 transgenic mice and cell lines expressing bcl-2 vectors will be analyzed to investigate how Bcl-2 intersects with cell cycle control. 3. Impact on lymphopoiesis of a general and a specific inhibitor of apoptosis. While the baculovirus p35 protein, which inhibits multiple ICE-like cysteine proteases, may inhibit all apoptotic signals, a dominant-negative mutant of FADD, which transduces an apoptotic signal from CD95 and the related TNF receptor TNFR1, is probably more specific. Transgenic mice expressing each of these inhibitors will be generated to assess their effect on the development and censoring of T cells, as well as their oncogenic potential. 4. Characterization of apoptosis signalling pathways. Bcl-2 and CrmA, the cowpox virus inhibitor of ICE, provide reciprocal patterns of protection to lymphocytes, suggestive of two major apoptotic signaling pathways. Apparent synergy between Bcl-2 and CrmA in blocking CD95-induced apoptosis, suggestive of crosstalk between the pathways, will be explored by determining the role of p53 and the pattern of inhibition of recently discovered apoptotic transducers FADD, RIP and TRADD. 5. Influence of v-abl and cyclin D1 on apoptosis. In view of reports that v-abl can promote cell survival and that cyclin D1 can induce apoptosis, they shall investigate the survival capacity of lymphocytes expressing v-abl and cyclin D1 transgenes, both alone and together with other oncogenes.
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