Control of tissue growth and architecture by Drosophila Tsg101

果蝇 Tsg101 对组织生长和结构的控制

• 批准号: 7477112
• 负责人: Kenneth H Moberg
• 金额: $ 21.1万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477112
• 关键词: Architecture; Biochemical Genetics; Biological Models; Cell Cycle Regulation; Cell Polarity; Cells; Complex; Cyclin D1; Data; Defect; Development; Drosophila genus; Drosophila melanogaster; Endosomes; Epithelial; Etiology; Event; Eye; Genes; Genetic Techniques; Goals; Growth; Human; Hyperplasia; Insulin; Ligands; Malignant Neoplasms; Modeling; Molecular; Molecular Genetics; Mus; Mutation; Oncogenic; Organ; Orthologous Gene; Pathway interactions; Pattern; Phenotype; Proteins; Regulation; Regulatory Pathway; Research; Research Personnel; Shapes; Signal Pathway; System; Techniques; Testing; Tissues; Tsg101 protein; Tumor Suppressor Proteins; Work; base; cell growth; fly; human disease; in vivo; mutant; notch protein; programs; receptor expression; role model

DESCRIPTION (provided by applicant): The reproducible pattern of organismal growth during metazoan development is the product of genetically controlled signaling pathways/Patterned activation of these pathways shapes developing organs, and defects in their regulation can contribute to hyperplastic phenotypes like cancer. A long-term goal of our research program is to identify and characterize growth-inhibitory genes using the fruit fly Drosophila melanogaster as a model system of metazoan development. We anticipate that in some cases, these genes will encode the fly orthologs of mammalian tumor suppressors, and that our work will thus provide a model for the roles of these genes in human disease. One such gene, called Tumor susceptibility gene-101 (Tsg101), is the subject of the work proposed here. Almost ten years ago, it was shown that functional inactivation of Tsg101 causes cultured mouse cells to display features of oncogenic transformation. However, the mechanisms underlying this effect have remained very poorly understood. Recently, we isolated mutations in the Drosophila ortholog of the human Tsg101 gene (referred to as Tsg101) based upon their surprising ability to provoke overgrowth phenotypes in the developing fly eye. Using this system as a model of Tsg101 function, we have identified two downstream targets of Tsg101 mutations: one is a non-cell autonomous pathway involving ectopic activation of the Notch receptor and expression of unpaired, the secreted ligand of the Jak-STAT pathway; the second involves the Crumbs protein, an established component of cell polarity regulatory complexes, and is associated with cell-autonomous defects in epithelial polarity and tissue architecture. The aims of this proposal are an extension of these findings. Notch appears to be a critical effector of Tsg101 mutant phenotypes, and in Aim 1, we will investigate the molecular mechanism through which Tsg101 mutations activate the Notch receptor. In Aim 2, we propose to investigate the mechanism through which Tsg101 controls Crumbs, and to use genetic techniques test the hypothesis that Tsg101 mutations alter Crumbs activity in vivo. And in Aim 3, we will use genetic and biochemical techniques to test the hypothesis that Tsg101 mutations trigger eye hyperplasia by activating one or more of the major growth regulatory pathways in Drosophila (Tsc/Tor, insulin, Ras, Myc, and CyclinD).

描述(申请人提供)：后生动物发育过程中生物生长的可复制模式是由基因控制的信号通路/这些通路的模式激活形成发育中的器官的产物，它们调控的缺陷可能导致癌症等增生性表型。我们研究计划的一个长期目标是利用果蝇黑腹果蝇作为后生动物发育的模式系统来识别和表征生长抑制基因。我们预计，在某些情况下，这些基因将编码哺乳动物肿瘤抑制基因的同源基因，因此我们的工作将为这些基因在人类疾病中的作用提供一个模型。一个这样的基因，被称为肿瘤易感基因-101(Tsg101)，是这里提出的工作的主题。近十年前，研究表明，Tsg101的功能失活会导致培养的小鼠细胞出现致癌转化的特征。然而，这种效应背后的机制仍然知之甚少。最近，我们分离出了人类Tsg101基因的果蝇直系同源基因(称为Tsg101)的突变，这是基于它们惊人的能力在发育中的苍蝇眼中引发过度生长的表型。利用这个系统作为Tsg101功能的模型，我们已经确定了Tsg101突变的两个下游靶点：一个是非细胞自主途径，涉及Notch受体的异位激活和Jak-STAT途径的分泌配体Unpared的表达；第二个涉及Crumbs蛋白，它是细胞极性调节复合体的既定成分，与上皮极性和组织结构的细胞自主缺陷有关。这项提议的目的是这些发现的延伸。Notch似乎是Tsg101突变表型的关键效应因子，在目标1中，我们将研究Tsg101突变激活Notch受体的分子机制。在目标2中，我们建议研究Tsg101控制Crumbs的机制，并利用基因技术检验Tsg101突变改变体内Crumbs活性的假设。在目标3中，我们将使用遗传和生化技术来验证Tsg101突变通过激活果蝇中一个或多个主要生长调节通路(TSC/Tor、胰岛素、RAS、Myc和CylinD)而引发眼部增生的假说。