Mechanisms of Drosophila Tumor Suppression

果蝇肿瘤抑制机制

• 批准号: 8511701
• 负责人: David Bilder
• 金额: $ 26.12万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511701
• 关键词: Adult; Animals; Architecture; Biological Models; Biology; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Chromatin; Clinical; Control Groups; Data; Development; Dimensions; Drosophila genus; Ensure; Epigenetic Process; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; F-Box Proteins; Family; Gene Mutation; Genes; Genetic; Genetic Screening; Genome; Goals; Growth; Human; Intervention; Ligands; Light; Limb structure; Malignant Neoplasms; Molecular; Natural regeneration; Organ; Organ Size; Pathway interactions; Polycomb; Process; Regulation; Regulatory Pathway; Retinal blind spot; Role; System; Testing; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vertebrates; Work; Wound Healing; X Chromosome; base; design; fly; gene cloning; genome wide association study; imaginal disc; insight; mutant; neoplastic; neoplastic cell; novel; prevent; public health relevance; restraint; scaffold; tumor; ubiquitin ligase; ubiquitin-protein ligase; upstream kinase

DESCRIPTION (provided by applicant): The mechanisms by which organs control cell proliferation to reach an appropriate final size during development and regeneration are a central question of biology, and are also critical to an understanding of cancer. Despite intensive work on this question, we currently appreciate only a fraction of these mechanisms. Comprehensive identification of organ growth control pathways will be required as a precursor to 'systems'-level understanding, and will also open up new avenues for manipulation and clinical intervention. Drosophila has become a favorite model system for understanding the basic cellular functions and intercellular interactions by which organ dimensions are determined. The identification of Drosophila 'tumor suppressor genes (TSGs)', mutations in which cause cells and/or organs to overproliferate, has provided both mechanistic insight into known pathways as well as the identification of completely new organ size control pathways that appear conserved in vertebrates. Several extensive screens for fly TSGs have been carried out, but these have a significant blind spot: they rely on survival and appropriate differentiation of the cells in the adult, as well as adult survival of the tumor- containing animal. We have designed and executed a novel genetic screen ('MENE') that isolates a previously inaccessible set of potent TSGs, mutations in which cause lethal and often disorganized overgrowth of poorly differentiated imaginal disc cells ('neoplastic TSGs'). In this proposal, we will use new mutants from the MENE screen as an entry point to study two distinct cellular functions with unappreciated roles in restraining tissue growth. The first involves epigenetic control of growth by the Polycomb Group (PcG) family of chromatin regulators. The second involves a ubiquitin ligase that regulates both cell proliferation and epithelial polarity. We will determine the mechanism of growth restraint for these TSGs, and integrate their activities into known pathways controlling disc growth. Finally, we will extend the genome-wide screen for neoplastic TSGs, in order to identify additional pathways that restrain disc cell proliferation and elucidate the common mechanisms that underlie all neoplastic TSG activities. Together, these studies will advance our long-term goal of understanding the entire constellation of cellular processes by which organs control their growth and prevent tumor formation. PUBLIC HEALTH RELEVANCE: The mechanisms by which organs control cell proliferation to reach an appropriate final size are a central question of biology, and are also critical to an understanding of cancer. Drosophila provides a simple model system ideal for unbiased, genome-wide identification of genes that prevent cellular overproliferation. This proposal will elucidate how two new and unappreciated cellular mechanisms function and interact with other known mechanisms to ensure proper tissue growth in the fly, and identify further novel growth-control mechanisms that are likely to be conserved in humans.

描述（由申请人提供）：器官控制细胞增殖以在发育和再生过程中达到适当最终大小的机制是生物学的核心问题，对于对癌症的理解也至关重要。尽管在这个问题上进行了大量工作，但我们目前仅感谢这些机制的一小部分。将需要对器官生长控制途径进行全面识别，以作为“系统”级别理解的先驱，还将为操纵和临床干预提供新的途径。果蝇已成为理解基本细胞函数和确定器官尺寸的细胞间相互作用的模型系统。果蝇“肿瘤抑制基因（TSG）的鉴定”突变，导致细胞和/或器官过度增殖，这两种机械洞察力都可以洞悉已知途径，并鉴定了出现在脊椎动物中保守的全新器官大小控制途径。已经进行了几个针对Fly TSG的广泛筛选，但是它们具有一个很大的盲点：它们依赖于成人细胞的生存和适当的分化，以及含有肿瘤的动物的成人生存。我们设计并执行了一种新型的遗传筛选（“ mene”），该筛查分离了以前无法访问的有效TSG集，其中会导致致命且经常混乱的过度生长，以分化不良的想象盘细胞（'Neoplastic TSGS'）。在此提案中，我们将使用来自Mene屏幕的新突变体作为入口点，以研究两个不同的细胞功能，在限制组织生长中具有未引人注目的作用。第一个涉及多肉液组（PCG）染色质调节剂对生长的表观遗传控制。第二个涉及一个泛素连接酶，可调节细胞增殖和上皮极性。我们将确定这些TSG的生长限制机理，并将其活性整合到控制圆盘生长的已知途径中。最后，我们将扩展肿瘤TSG的全基因组筛选，以确定抑制椎间盘细胞增殖的其他途径并阐明所有肿瘤TSG活性的共同机制。总之，这些研究将促进我们的长期目标，以了解器官控制其生长并防止肿瘤形成的整个细胞过程。 公共卫生相关性：器官控制细胞增殖以达到适当最终大小的机制是生物学的核心问题，对于对癌症的理解也至关重要。果蝇提供了一个简单的模型系统，非常适合对防止细胞过度增殖的基因的无偏，全基因组鉴定。该建议将阐明两种新的和未批准的细胞机制如何发挥作用并与其他已知机制相互作用，以确保苍蝇的适当组织生长，并确定可能在人类中可能保存的进一步的新型生长控制机制。