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

• 批准号: 7920567
• 负责人: RORY A. FISHER
• 金额: $ 20.76万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920567
• 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; abstracting; 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

Project Summary / Abstract RGS (Regulator of G protein Signaling) proteins represent a novel protein family believed to function as GTPase-activating proteins (GAPs) for heterotrimeric G protein ¿ 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.

项目总结/摘要 RGS（Regulator of G protein Signaling，G蛋白信号调节器）蛋白代表了一种新的蛋白质家族，据信其功能是 GTPase-activating proteins（GAP），用于异源三聚体G蛋白亚基，从而负调节细胞内的蛋白质。 G蛋白信号传导的持续时间和强度。关于所有这些基因的确切生理作用， 但是一些RGS蛋白，如果这些蛋白质起作用，为什么存在近三十种不同的哺乳动物RGS蛋白质 仅作为GAP，或负责的标志性RGS结构域（RGD）之外的结构多样性的作用 RGS蛋白GAP活性。GPCR和G蛋白的异常激活已经被认为是导致GPCR异常的原因。 各种人类癌症。因此，令人惊讶的是，RGS蛋白以前没有被考虑过。 作为生长或肿瘤抑制蛋白。在这里，我们提供了新的证据，表明这样一个成员的作用 RGS 6是RGS蛋白家族的成员，它以36种剪接形式存在，具有相同的RGDs， 其他蛋白质结构域的结构变异。具有RGS 6多态性的人，其增加mRNA 翻译有显着降低膀胱癌的风险，RGS 6的转录下降- 在各种人类癌症中受到调节。我们的初步数据显示RGS 6蛋白表达缺失或 相对于正常组织，在人类神经胶质瘤和乳腺癌中大大减少，并已鉴定出两种RGS 6 人类胶质母细胞瘤细胞中的突变体。RGS 6在癌细胞系中的表达，所述癌细胞系缺乏或表达 异常分子形式RGS 6，导致生长抑制、细胞周期停滞、信号传导激活 在DNA损伤过程中防止异常细胞增殖和抑制肿瘤生长的途径 异种移植我们假设RGS 6在保护细胞免受异常的细胞凋亡中起重要作用。 增殖，并且其缺失或突变有助于肿瘤形成。目标1将确定RGS 6的作用 作为肿瘤抑制剂和DNA损伤反应的调节剂。我们将确定RGS 6基因表达 在人类癌症中失调，以及其能力所需的结构特征和蛋白质相互作用 抑制肿瘤生长。目的2将确定RGS 6促进生长的分子机制 阻止并调节细胞中的DNA损伤信号。我们将确定RGS 6的结构特征， 参与生长抑制、细胞周期阻滞和DNA损伤调节的信号通路 我们将测试RGS 6在细胞核中的新功能作用，而G蛋白不是 礼物目的3将确定RGS 6的整体缺失或缺失在小鼠乳腺组织或胶质细胞中的作用 调节肿瘤发生。拟议的研究将提供新的结构和机制的见解， RGS 6作为生长抑制剂的作用及其在体内作用的生物学表现。这个项目 可能涉及RGS 6和其他RGS蛋白作为G蛋白依赖性肿瘤发生的守门人， 定义RGS 6在此过程中的新作用。这些研究可能有助于癌症的新方法 疗法项目叙述 该项目将研究一种名为RGS 6的蛋白质的作用，这种蛋白质可能具有预防人类癌症的功能。我们 初步结果使我们假设RGS 6在保护细胞免受 异常增殖，其缺失或突变导致人类肿瘤。这项工作将决定 RGS 6是如何工作的，并将决定人类癌症中RGS 6表达缺失的基础。这些研究 可能有助于癌症治疗的新方法。