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Molecular Analysis and Role of RGS6 as a Novel Growth Suppressor

RGS6 作为新型生长抑制剂的分子分析和作用

基本信息

批准号：
7920779
负责人：
RORY A. FISHER
金额：
$ 29.7万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-04-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920779
关键词：
ATM activation Abnormal Cell Binding Biological Cancer cell line Cell Cycle Arrest Cell Nucleus Cells DNA Damage Data GTP-Binding Protein Regulators GTP-Binding Proteins GTPase-Activating Proteins Gatekeeping Gene Expression Genes Genetic Polymorphism Genetic Translation Glioblastoma Glioma Growth Heterotrimeric GTP-Binding Proteins Human Lead Malignant Neoplasms Malignant neoplasm of urinary bladder Mammary gland Mediating Molecular Molecular Analysis Mus Mutation Neuroglia Normal tissue morphology Physiological Play Process Protein Family Proteins RGS Domain RGS Proteins RNA Splicing Relative (related person)Research Research Project Grants Risk Role Signal Pathway Signal Transduction Site System Tertiary Protein Structure Testing Tissues Transcript Tumor Suppression Tumor Suppressor Proteins Variant Work Yeasts base cancer therapy in vivo insight malignant breast neoplasm member mutant novel novel strategies prevent protein expression protein function response tumor tumor growth tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): RGS (Regulator of G protein Signaling) proteins represent a novel protein family believed to function as GTPase-activating proteins (GAPs) for heterotrimeric G protein 1 subunits, thereby negatively regulating the duration and intensity of G protein signaling. Little is known concerning the precise physiological roles of all but a few RGS proteins, why nearly thirty different mammalian RGS proteins exist if these proteins function only as GAPs, or the role of structural diversity outside of the hallmark RGS domain (RGD) responsible for RGS protein GAP activity. Abberant activation of GPCRs and G proteins has been implicated as a cause of a variety of human cancers. Therefore, it is surprising that RGS proteins have not been considered previously as growth or tumor suppressor proteins. Here we provide new evidence suggesting such a role for a member of the RGS protein family, RGS6, which exists in thirty-six splice forms possessing identical RGDs but structural variations in other protein domains. Humans with an RGS6 polymorphism that increases mRNA translation have a significant reduction in the risk of bladder cancer, and transcripts of RGS6 are down- regulated in various human cancers. Our preliminary data show that RGS6 protein expression is absent or greatly reduced in human glioma and breast cancer relative to normal tissue, and have identified two RGS6 mutants in human glioblastoma cells. Expression of RGS6 in cancer cell lines, which either lack or express aberrant molecular forms RGS6, leads to growth suppression, cell cycle arrest, activation of signaling pathways during DNA damage that prevent proliferation of abnormal cells, and inhibition of growth of tumor xenografts. We hypothesize that RGS6 plays an important role in protecting cells against abnormal proliferation and that its loss or mutation contributes to tumor formation. Aim 1 will ascertain the role of RGS6 as a tumor suppressor and modulator of DNA damage responses. We will identify how RGS6 gene expression is dysregulated in human cancers and the structural features and protein interactions required for its ability to suppress tumor growth. Aim 2 will determine the molecular mechanisms by which RGS6 promotes growth arrest and modulates DNA damage signaling in cells. We will identify the structural features of RGS6 and signaling pathways involved in growth suppression, cell cycle arrest and modulation of DNA damage responses by RGS6 and we will test novel functional roles of RGS6 in the nucleus where G proteins are not present. Aim 3 will determine how global deletion of RGS6 or deletion in mammary tissue or glial cells of mice modulates tumorigenesis. The proposed research would provide new structural and mechanistic insights into the role of RGS6 as a growth suppressor and the biological manifestations of its actions in vivo. This project may implicate RGS6 and other other RGS proteins as gatekeepers to G-protein-dependent tumorigenesis or define novel roles of RGS6 in this process. These studies could contribute to novel approaches in cancer therapy. PROJECT NARRATIVE: This project will study the role of a protein called RGS6 that may function to prevent cancer in humans. Our preliminary results lead us to hypothesize that RGS6 plays an important role in protecting cells against abnormal proliferation and that its loss or mutation contributes to tumors in humans. This work will determine how RGS6 works and will determine the basis for loss of RGS6 expression in human cancers. These studies could contribute to novel approaches in cancer therapy.

描述（由申请人提供）：RGS（G 蛋白信号传导调节剂）蛋白代表了一种新的蛋白家族，据信其作为异三聚体 G 蛋白 1 亚基的 GTP 酶激活蛋白（GAP）发挥作用，从而负向调节 G 蛋白信号传导的持续时间和强度。关于除少数 RGS 蛋白之外的所有 RGS 蛋白的精确生理作用，我们知之甚少；如果这些蛋白仅起 GAP 的作用，为什么存在近 30 种不同的哺乳动物 RGS 蛋白；或者负责 RGS 蛋白 GAP 活性的标志性 RGS 结构域 (RGD) 之外的结构多样性的作用。 GPCR 和 G 蛋白的异常激活已被认为是多种人类癌症的原因。因此，令人惊讶的是，RGS 蛋白以前并未被认为是生长或肿瘤抑制蛋白。在这里，我们提供了新的证据，表明 RGS 蛋白家族的成员 RGS6 具有这样的作用，RGS6 以 36 种剪接形式存在，具有相同的 RGD，但其他蛋白结构域存在结构变异。具有增加 mRNA 翻译的 RGS6 多态性的人类患膀胱癌的风险显着降低，并且 RGS6 的转录物在各种人类癌症中下调。我们的初步数据表明，相对于正常组织，人胶质瘤和乳腺癌中RGS6蛋白表达缺失或大大减少，并且在人胶质母细胞瘤细胞中鉴定出两种RGS6突变体。 RGS6 在缺乏或表达异常分子形式 RGS6 的癌细胞系中表达，会导致生长抑制、细胞周期停滞、DNA 损伤期间信号通路的激活（防止异常细胞增殖）以及肿瘤异种移植物生长的抑制。我们假设 RGS6 在保护细胞免受异常增殖方面发挥重要作用，并且它的丢失或突变有助于肿瘤的形成。目标 1 将确定 RGS6 作为肿瘤抑制因子和 DNA 损伤反应调节剂的作用。我们将确定 RGS6 基因表达在人类癌症中如何失调，以及其抑制肿瘤生长的能力所需的结构特征和蛋白质相互作用。目标 2 将确定 RGS6 促进细胞生长停滞和调节 DNA 损伤信号传导的分子机制。我们将鉴定 RGS6 的结构特征以及参与 RGS6 生长抑制、细胞周期停滞和 DNA 损伤反应调节的信号通路，并且我们将测试 RGS6 在不存在 G 蛋白的细胞核中的新功能作用。目标 3 将确定 RGS6 的整体缺失或小鼠乳腺组织或神经胶质细胞的缺失如何调节肿瘤发生。拟议的研究将为 RGS6 作为生长抑制剂的作用及其体内作用的生物学表现提供新的结构和机制见解。该项目可能暗示 RGS6 和其他 RGS 蛋白作为 G 蛋白依赖性肿瘤发生的看门人，或定义 RGS6 在此过程中的新作用。这些研究可能有助于癌症治疗的新方法。项目叙述：该项目将研究一种名为 RGS6 的蛋白质的作用，该蛋白质可能有助于预防人类癌症。我们的初步结果使我们假设 RGS6 在保护细胞免受异常增殖方面发挥着重要作用，并且它的缺失或突变会导致人类肿瘤。这项工作将确定 RGS6 的工作原理，并将确定人类癌症中 RGS6 表达缺失的基础。这些研究可能有助于癌症治疗的新方法。