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: 7901473
• 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/7901473
• 关键词: Architecture; Biochemical; 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; 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（由申请人提供）：后生动物发育期间生物体生长的可再现模式是遗传控制的信号传导途径的产物/这些途径的模式化激活塑造发育中的器官，并且其调节中的缺陷可能导致增生表型，如癌症。我们的研究计划的一个长期目标是确定和表征生长抑制基因使用果蝇作为后生动物发育的模型系统。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果蝇直系同源物，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，称为肿瘤易感基因-101（Tsg 101），是这里提出的工作的主题。大约十年前，研究表明Tsg 101的功能失活导致培养的小鼠细胞显示致癌转化的特征。然而，这种影响的机制仍然知之甚少。最近，我们在果蝇的人类Tsg 101基因（简称Tsg 101）的直系同源基因中分离出突变，这是基于它们在发育中的蝇眼中引起过度生长表型的惊人能力。使用该系统作为Tsg 101功能的模型，我们已经确定了Tsg 101突变的两个下游靶点：一个是涉及Notch受体的异位激活和Jak-STAT途径的分泌配体未配对的表达的非细胞自主途径;第二个涉及Crumbs蛋白，一种细胞极性调节复合物的确定组分，并且与上皮极性和组织结构中的细胞自主缺陷有关。本提案的目的是这些调查结果的延伸。Notch似乎是Tsg 101突变表型的关键效应子，在目标1中，我们将研究Tsg 101突变激活Notch受体的分子机制。在目标2中，我们建议研究Tsg 101控制Crumbs的机制，并使用遗传技术测试Tsg 101突变改变Crumbs体内活性的假设。在目标3中，我们将使用遗传和生物化学技术来验证Tsg 101突变通过激活果蝇中的一种或多种主要生长调节途径（Tsc/Tor，胰岛素，Ras，Myc和CyclinD）来触发眼增生的假设。