Function of the Drosophila Myb Proto-Oncogene

描述(申请人提供)：已在哺乳动物、鸟类和两栖动物中鉴定出三个Myb相关基因(c-Myb、A-Myb和B-Myb)。C-Myb是禽成髓细胞增多症病毒和E26白血病病毒中存在的v-Myb逆转录病毒癌基因的细胞同源物。C-Myb对小鼠的胎儿造血是必不可少的，c-Myb的变化形式会导致哺乳动物和鸟类的白血病和淋巴瘤。A-Myb是小鼠精子发生和乳腺增殖所必需的。与c-Myb和A-Myb的组织特异性功能不同，B-Myb似乎在脊椎动物的所有分裂细胞中都有表达，其水平在侵袭性人类癌症中升高。B-Myb基因在小鼠体内的破坏会导致非常早期的胚胎死亡。海胆和果蝇有单一的Myb相关基因，与脊椎动物B-Myb最相似。我们最近通过P元件动员产生了两个新的果蝇Myb非条件性突变等位基因(DM-Myb)。这两个等位基因都在三龄后期幼虫/预蛹死亡，成像盘发育大大延迟。我们的初步数据显示，DM-Myb功能的丧失导致有丝分裂组织的M期停滞，非整倍体和多倍体增加，而不是其他人基于ts突变体的研究报告的G2期停滞。此外，我们还发现，正常情况下缺乏有丝分裂的卵巢滋养细胞需要DM-Myb，而卵巢卵泡细胞需要DM-Myb来扩增绒毛基因。后者的发现非常有趣，因为果蝇绒毛膜基因包含高等真核生物基因组DNA复制的最具特征的起源。我们现在建议使用各种遗传和生化工具来进一步分析DM-Myb如何在正常生长和分化过程中调节细胞周期。特别是，我们建议确定DM-Myb在以下过程中的特殊作用：(1)幼虫脑和成像盘中典型的G1/S/G2/M细胞周期；(2)早期胚胎中快速的S/M周期；(3)多倍体组织的G/S内周期；(4)绒毛膜基因扩增的专化S期；以及(5)配子发生，这需要生殖系孢囊形成和减数分裂的不完全有丝分裂。

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.