Function of the Drosophila Myb Proto-Oncogene

描述（由申请人提供）：已在哺乳动物、鸟类和两栖动物中鉴定出三种 Myb 相关基因（c-Myb、A-Myb 和 B-Myb）。 c-Myb 是存在于禽类成髓细胞瘤病毒和 E26 白血病病毒中的 v-Myb 逆转录病毒癌基因的细胞同源物。 c-Myb 对于小鼠胎儿造血至关重要，而 c-Myb 的改变形式会导致哺乳动物和鸟类患白血病和淋巴瘤。 A-Myb 是小鼠精子发生和乳腺增殖所必需的。与 c-Myb 和 A-Myb 的组织特异性功能相反，B-Myb 似乎在脊椎动物的所有分裂细胞中表达，并且其水平在侵袭性人类癌症中升高。小鼠 B-Myb 的破坏会导致早期胚胎死亡。海胆和果蝇具有与脊椎动物 B-Myb 最相似的单一 Myb 相关基因。 我们最近通过 P 元件动员产生了果蝇 Myb (Dm-Myb) 的两个新的非条件突变等位基因。两个等位基因均在三龄幼虫/预蛹时死亡，成虫盘发育大大延迟。我们的初步数据表明，Dm-Myb 功能的丧失会导致有丝分裂组织的 M 期停滞，并增加非整倍性和多倍性，而不是其他人之前基于 ts 突变体研究报道的 G2 停滞。此外，我们发现 Dm-Myb 在卵巢护理细胞中是正常缺乏有丝分裂的正常内周期所必需的，在卵巢滤泡细胞中是为了绒毛膜基因扩增所必需的。后一个发现非常令人感兴趣，因为果蝇绒毛膜基因包含高等真核生物中基因组 DNA 复制的最佳特征起点。我们现在建议使用多种遗传和生化工具来进一步分析 Dm-Myb 在正常生长和分化过程中如何调节细胞周期。特别是，我们建议确定 Dm-Myb 在以下方面的具体作用：（1）幼虫大脑和成虫盘中的典型 G1/S/G2/M 细胞周期； (2)早期胚胎的快速S/M周期； (3)多倍体组织的G/S内环； (4)绒毛膜基因扩增的特化S期； (5)配子发生，需要种系包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.