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Characterization of a novel TGF-beta signaling component

新型 TGF-β 信号传导成分的表征

基本信息

批准号：
6806195
负责人：
THEODOR E HAERRY
金额：
$ 19.25万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2007-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6806195
关键词：
Drosophilidae RNA interference activins alleles arthropod genetics biological signal transduction gene complementation gene mutation genetic screening membrane proteins phenotype protein isoforms protein structure function transcription factor transforming growth factors

项目摘要

DESCRIPTION (provided by applicant): Characterization of a novel membrane protein potentially involved in TGF-Beta signaling In both flies and vertebrates, members of the TGF-B family of growth factors play prominent roles in embryonic pattern formation and in the regulation of cell growth and proliferation. In humans, there are many strong links between mutations in various components of TGF-Beta signaling pathways and tumor formation. In recent years, a lot of progress has been made toward understanding the mechanism of TGF-B signaling and cell cycle arrest. However, the mechanisms, how Activins and TGF-Betas can promote and inhibit cell proliferation in different tissues, are not known. Drosophila contains substantially fewer genes than vertebrate genomes. It only encodes seven TGF-Beta-type ligands signaling through three type I receptor and two SMAD transcription factors. We find that two of the ligands, dActivin and Anti-Activin, signal through the same type 1/11receptors and activate both dSMAD1 (MAD), which is primarily activated by DPP, and dSMAD2. However, the two ligands exhibit opposite effects in vivo. When overexpressed in wings, dActivin signaling through dSMAD1 promotes growth, while Anti-Activin also signaling through dSMAD1 inhibits growth. This result indicates that the TGF-Beta signaling pathway may be more complex than the characterized type VII receptor/SMAD pathway. In this proposal, we describe a new type of membrane protein that may function in TGF-Beta signaling. In a genetic screen, we have isolated a mutation that strongly interacts with DPP signaling similarly to dSMAD1 and Medea. Our analysis suggests that the mutated gene most likely encodes an evolutionary highly conserved gene that encodes a transmembrane protein with multiple isoforms. We have obtained at least four alleles of this gene from EMS mutagenesis screens and an additional allele by P-element mobilization. The strongest allele is embryonic lethal, and homozygous clones are cell-lethal. The goal of this proposal is to prove that these phenotypes are caused by mutations in this novel transmembrane protein and to characterize the molecular nature of individual mutant alleles. This project has great potential to contribute new insights into the mechanism of TGF-Beta signaling and our understanding of the development of certain cancers. It may also provide a new target to combat these diseases.

描述(由申请人提供)：一种可能参与果蝇和脊椎动物转化生长因子-β信号转导的新的膜蛋白的特征，转化生长因子-β家族的成员在胚胎模式形成和细胞生长和增殖调节中发挥重要作用。在人类中，转化生长因子-β信号通路各组成部分的突变与肿瘤的形成之间有许多强烈的联系。近年来，对转化生长因子-β信号转导和细胞周期停滞机制的研究取得了很大进展。然而，激活素和转化生长因子-β如何在不同组织中促进和抑制细胞增殖的机制尚不清楚。果蝇包含的基因比脊椎动物的基因组少得多。它只编码7个通过3个I型受体和2个SMAD转录因子传递信号的转化生长因子-β配体。我们发现其中两个配体dActivin和anti-Activin通过相同的1/11受体发出信号，并激活主要由DPP激活的dSMAD1(MAD)和dSMAD2。然而，这两种配体在体内表现出相反的作用。当dActivin在翅膀中过表达时，dActivin通过dSMAD1信号促进生长，而Anti-Activin也通过dSMAD1信号抑制生长。这一结果表明，转化生长因子-β信号通路可能比特征性的VII型受体/SMAD信号通路更为复杂。在这个提案中，我们描述了一种新型的膜蛋白，它可能在转化生长因子-β信号转导中发挥作用。在基因筛查中，我们分离出了一种与DPP信号强烈相互作用的突变，类似于dSMAD1和MedeA。我们的分析表明，突变的基因很可能编码一个进化上高度保守的基因，编码一种具有多种异构体的跨膜蛋白。我们通过EMS诱变筛选获得了该基因的至少4个等位基因，并通过P元件动员获得了另外1个等位基因。最强的等位基因是胚胎致死的，而纯合子克隆是细胞致死的。这一建议的目的是证明这些表型是由这种新型跨膜蛋白的突变引起的，并表征单个突变等位基因的分子性质。这个项目有很大的潜力为转化生长因子-β信号的机制和我们对某些癌症发展的理解提供新的见解。它还可能为抗击这些疾病提供一个新的目标。