Function of the Drosophila Myb Proto-Oncogene

果蝇 Myb 原癌基因的功能

• 批准号: 7096443
• 负责人: Joseph Steven Lipsick
• 金额: $ 7.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096443
• 关键词: Drosophilidae; arthropod genetics; cell cycle; cell growth regulation; cell proliferation; cytogenetics; developmental genetics; hematopoiesis; immunoregulation; invertebrate embryology; laboratory rabbit; oncogenes; protooncogene; spermatogenesis

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.

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对于小鼠中的胎儿造血是必需的，并且c-Myb的改变形式在哺乳动物和鸟类中引起白血病和淋巴瘤。A-Myb是小鼠精子发生和乳腺增生所必需的。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，并且其水平在人类癌症的侵袭性形式中升高。小鼠中B-Myb的破坏导致非常早期的胚胎致死。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元件移动产生了两个新的果蝇Myb基因的非条件突变等位基因（Dm-Myb）。这两个等位基因死亡的晚三龄幼虫/包皮的成虫盘发育大大延迟。我们的初步数据表明，Dm-Myb功能的丧失导致有丝分裂组织中M期阻滞，非整倍体和多倍体增加，而不是G2阻滞，如先前基于TS-突变体的研究的其他人所报道的。此外，我们还发现Dm-Myb在正常情况下缺乏有丝分裂的卵巢滋养细胞和卵巢卵泡细胞中是绒毛膜基因扩增所需的。后一个发现非常有趣，因为果蝇绒毛膜基因包含高等真核生物中最具特征的基因组DNA复制起点。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在正常生长和分化过程中如何调节细胞周期。特别是，我们拟确定Dm-Myb在以下方面的特异性作用：（1）幼虫脑和成虫盘的典型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内周期，（4）绒毛膜基因扩增的特化S期，（5）胚胎发育的早期S/M期。（5）配子发生，需要生殖细胞包囊形成和减数分裂的不完全有丝分裂。