The broad aim of this project is to use genetically modified mice to clarify the roles of opposing factions of the Bcl2 family in apoptosis and malignancy. The principal focus will be pro-apoptotic relatives known as BH3-only proteins: (i) Mice lacking expression of one or more BH3-only proteins will be characterized for phenotypic abnormalities and apoptotic defects, particularly in lymphoid, myeloid and erythroid cells and their progenitors and in embryonic fibroblasts, and for tumor susceptibility. (ii) The responsiveness of the different cell types to radiation and chemotherapeutics will be determined, to identify the key BH3-only proteins involved in triggering apoptosis during cytotoxic cancer therapies. (iii) BHS-only -/- mice will be crossed with Ipr/lpr mice, which lack functional Fas, to determine which BH3-only proteins synergize with the Fas death receptor in curbing expansion of cell compartments. (iv) puma-/-noxa-/- mice and puma-/-p21-/- mice will be generated to assess whether the combined loss of these p53 targets will create tumor-prone mice akin to p53-/- mice. (v) Following up the recent discovery that Bim suppresses Myc-induced acute B cell leukemia, bim -/- mice will be crossed to newly developed transgenic mice with constitutive pan-hematopoietic expression of Myc, to ascertain whether loss of Bim accelerates other hematopoietic malignancies. (vi) To see if Puma and Noxa are also tumor suppressors, similar crosses will be performed between Myc transgenic mice and puma-/- and noxa-/- mice. (vii) To assess whether loss of Bim, Noxa or Puma accelerates malignant transformation of plasma cells, crosses will be performed between plasmacytoma-prone v-ab/ mice and BH3-only 'knockout' mice. As these studies build upon a productive ongoing program, address major issues concerning apoptosis and leukemogenesis, and exploit unique resources, they should greatly enhance understanding of how apoptosis controls homeostasis and how impairment of this vital cellular process contributes to cancer and limits cancer therapy.
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