Function of the Drosophila Myb Proto-Oncogene

Stanford University, Stanford CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Three Myb-related genes (c-Myb, A-Myb, and B-Myb) have been identified in mammals, birds, and amphibians. c-Myb is the cellular homologue of the v-Myb retroviral oncogene that is present in the avian myeloblastosis virus and the E26 leukemia virus. c-Myb is essential for fetal hematopoiesis in mice and altered forms of c-Myb cause leukemias and lymphomas in mammals and birds. A-Myb is required for spermatogenesis and for mammary gland proliferation in mice. In contrast to the tissue-specific functions of c-Myb and A-Myb, B-Myb appears to be expressed in all dividing cells in vertebrates, and its levels are elevated in aggressive forms of human cancer. Disruption of B-Myb in the mouse results in very early embryonic lethality. The sea urchin and the fruit fly have single Myb-related genes most similar to vertebrate B-Myb. We have recently generated two new non-conditional mutant alleles of Drosophila Myb (Dm-Myb) by P element mobilization. Both alleles die as late third instar larvae/ prepupae with greatly delayed imaginal disc development. Our preliminary data show that loss of Dm-Myb function results in M phase arrest in mitotic tissues with increased aneuploidy and polyploidy, rather than G2 arrest as previously reported by others based on studies of ts-mutants. In addition, we have found that Dm-Myb is required in ovarian nurse cells for proper endocycles that normally lack mitoses and in ovarian follicle cells for chorion gene amplification. The latter finding is of great interest because Drosophila chorion genes contain the best-characterized origins of genomic DNA replication in higher eukaryotes. We now propose to use a variety of genetic and biochemical tools to further analyze how Dm-Myb regulates the cell cycle during normal growth and differentiation. In particular, we propose to determine the specific role of Dm-Myb in: (1) the canonical G1/S/G2/M cell cycle in larval brain and imaginal discs; (2) the rapid S/M cycle in early embryos; (3) the G/ S endocycles of polyploid tissues; (4) the specialized S phase of chorion gene amplification; and (5) gametogenesis, which requires the incomplete mitoses of germline cyst formation and meiosis.