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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：
8458103
负责人：
RORY A. FISHER
金额：
$ 28.1万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-10 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458103
关键词：
Abnormal Cell Apoptosis Biological Markers Bladder Bladder Neoplasm Carcinogens Cell Proliferation DNA DNA Damage DNA Repair Data Diagnosis Diagnostic Doxorubicin Epigenetic Process Epithelial Cells Exhibits Family member GTP-Binding Protein Regulators GTP-Binding Proteins Genes Genetic Genotoxic Stress Grant Growth Health Heterotrimeric GTP-Binding Proteins Human Incidence Knockout Mice Laboratories Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of urinary bladder Mediator of activation protein MicroRNAs Mitochondria Molecular Molecular Analysis Morbidity - disease rate Mus Mutation Oncogene Activation Oncogenic Pathogenesis Pathway interactions Patients Predisposition RGS Proteins Reactive Oxygen Species Recurrence Risk Risk Factors Role Signal Transduction Single Nucleotide Polymorphism Smoker Smoking Stimulus Tobacco smoke Translations Tumor Suppression Tumor Suppressor Proteins Tumorigenicity Up-Regulation Work base cancer genetics cancer risk carcinogenesis cell transformation in vivo innovation loss of function loss of function mutation member metaplastic cell transformation mortality mouse model neoplastic cell new therapeutic target novel outcome forecast prevent prognostic response therapeutic target tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Urinary bladder cancer is the fifth most common cancer in the U.S. and the most expensive cancer to treat on a per patient basis because of its high incidence of recurrence and the lack of effective, targeted therapeutics. An expected 70,000 patients will be diagnosed with and 15,000 patients will die of urinary bladder cancer in the U.S. this year alone. Despite the high incidence and lack of therapy for bladder cancer, the mechanisms of tumor initiation and progression are largely unknown. The greatest risk factor for bladder cancer is smoking, which promotes malignant transformation of transitional epithelial cells of the bladder by mechanisms involving DNA damage and oncogene activation. Here we provide the first evidence for entirely novel signaling actions of Regulator of G protein Signaling 6 (RGS6) as an essential mediator of p53 induction during genotoxic stress and as a tumor suppressor in bladder. RGS6 is dramatically induced by tumorigenic stimuli including genotoxic stress and oncogene activation. RGS6 functions as an upstream activator of the ATM-p53- apoptosis pathway yet also induces apoptosis, arrests cell proliferation and blocks oncogenic transformation of cells by p53-independent mechanisms. These actions of RGS6 are independent of its canonical function as a heterotrimeric G protein in activator. We previously described a single nucleotide polymorphism in RGS6, which leads to increased RGS6 translation, which is associated with a significant reduction in the risk of bladder cancer in humans, particularly in smokers. Given these findings, it is especially significant that we observed a dramatically accelerated bladder carcinogenesis and loss of p53 induction in RGS6 null mice in response to their treatment with BBN, a DNA-damaging carcinogen derived from tobacco smoke that induces bladder carcinogenesis in mice closely mimicking that observed in the majority of human patients. The robust expression of RGS6 we found in bladder transitional epithelial cells was dramatically lost in patients with invasive bladder cancer. Our central hypothesis, formulated on the basis of compelling preliminary data, is that RGS6 is a novel master regulator of both DNA damage signaling and tumor suppression in bladder. Three specific aims are proposed: 1) Determine the importance of RGS6 as a tumor suppressor in a mouse model of bladder carcinogenesis and the role of p53 and ARF in its tumor suppressor function, 2) Determine the underlying molecular mechanisms by which RGS6 functions as an upstream modulator of DNA damage signaling and as a tumor suppressor in bladder transitional epithelial cells, and 3) Determine the molecular basis for RGS6 loss in human bladder cancer. These aims seek to elucidate the role of RGS6 in suppression of bladder tumorigenesis and the underlying mechanisms involved. Loss of RGS6, as observed in human bladder tumors, or its mutational inactivation would be expected to confer tumor cells with a predisposition to aberrant growth and enhanced survival, hallmarks of malignancy. The significance of these studies to human health is great. They will provide new understanding of the pathogenesis of urinary bladder cancer and potentially identify RGS6 as a biomarker for the prognosis or diagnosis of bladder cancer as well as a new therapeutic target for its treatment.

描述（由申请人提供）：由于其高复发率和缺乏有效的靶向治疗方法，膀胱癌是美国第五大常见癌症，也是每位患者治疗费用最高的癌症。仅在美国，预计今年将有7万名患者被诊断患有膀胱癌，1.5万名患者将死于膀胱癌。尽管膀胱癌发病率高且缺乏治疗，但肿瘤发生和发展的机制在很大程度上是未知的。膀胱癌的最大危险因素是吸烟，吸烟通过DNA损伤和癌基因激活等机制促进膀胱移行上皮细胞的恶性转化。在这里，我们为G蛋白信号调节因子的全新信号作用提供了第一个证据