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Role of an RNA-Binding Protein in Mammary Carcinogenesis

RNA 结合蛋白在乳腺癌发生中的作用

基本信息

批准号：
7908176
负责人：
JEFFREY ROSS
金额：
$ 23.87万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-06 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7908176
关键词：
Actins Address Affect Binding Binding Proteins Birth Breast Adenocarcinoma Code Cytoplasm Deletion Mutation Doxycycline Environmental Risk Factor Epithelial Cells Female Fetal Tissues Gene Expression Genes Genetic Goals H19 RNA Harvest Histologic Human Incidence Insulin-Like Growth Factor II Knowledge Life Link Maintenance Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Messenger RNA Microarray Analysis Modeling Molecular Profiling Mus Neoplasms Nori Oncogene Proteins Oncogenic Other Genetics Pathway interactions Play Pongidae Preparation Process Property Protein Kinase Proteins Proto-Oncogenes RNA RNA Binding RNA-Binding Proteins Role Somatomedins Suppressor Genes System Testing Tetracyclines Time Tissues Transgenic Mice Translations Tumor Suppressor Genes Tumor Suppressor Proteins Untranslated Regions Work analog c-myc Genes chemical carcinogen fetal in vivo malignant breast neoplasm mouse model neoplastic novel transcription factor tumor tumorigenesis

项目摘要

This proposal investigates the role of an RNA-binding oncoprotein in mammary tumorigenesis. This protein is located in the cytoplasm and binds to insulin-like growth factor-ll, p-actin, c-myc, and other mRNAs. We call it the c-myc Coding Region instability Determinant-binding Protein or CRD-BP. because it binds to an instability determinant in the c-myc mRNA coding region. The CRD-BP affects RNA translation, stability, and localization, depending on the RNA to which it binds. It is expressed abundantly in fetaltissues but is repressed shortly after birth. Therefore, it probably has a special role in fetal life. Three findings also link the CRD-BP to breast cancer: (a) The CRD-BP is undetectable in normal breast tissue but is present in -60% of human breast tumors, (b) The CRD-BP gene is amplified in -30% of human breast tumors, (c) The CRD-BP induces mammary adenocarcinomas in female transgenic mice. Three aims use transgenic mice to investigate the pathways of mammary tumor induction by this RNA-binding oncoprotein. Aim I. Determine if CRD-BP expression is required continuously to maintain an existing mammary tumor. Mammary tumors in transgenic mice continue to express the CRD-BP and thus might be CRD-BP- dependent for their survival. To investigate this idea, Aim I exploits a mouse model in which mammary- specific CRD-BP expression is induced by doxycycline (dox), a tetracycline analog. Mammary tumors are expected to arise in dox-treated mice. Aim I then asks: Do these tumors stop growing or regress when dox is withdrawn? Our working hypothesis is that tumors will regress when CRD-BP expression is repressed. Aim II. Use microarray analysis to compare gene expression profiles in nori-neoplastic mammary tissues and in purified mammary epithelial cells of mice that do or do not express the CRD-BP. Some CRD- BP-regulated RNAs could play central roles in the induction and maintenance of mammary tumors. Aim III. Determine how genetic and environmental factors contribute to mammary tumorigenesis in CRD-BP-expressing mice. The goal is to assess how the tumor suppressor Ape and the chemical carcinogen N-ethyl-N-nitrosurea (ENU) affect CRD-BP-mediated tumor formation. We predict Apedeficiency and ENU treatment will synergize with the CRD-BP to increase tumor incidence and malignancy. Many of the well-studied oncoproteins are transcription factors or protein kinases. The CRD-BP is an unusual oncoprotein, because it resides in the cytoplasm and binds to RNA. By investigating the oncogenic properties of the CRD-BP, the RNAs it affects in vivo, and its interactions with tumor-inducing genetic and environmental factors, we hope to uncover novel tumorigenesis pathways.

本研究旨在探讨RNA结合癌蛋白在乳腺肿瘤发生中的作用。这蛋白质位于细胞质中并与胰岛素样生长因子-II、β-肌动蛋白、c-myc和其他 mRNA。我们称之为c-myc编码区不稳定性决定簇结合蛋白或CRD-BP。因为它与c-myc mRNA编码区的不稳定决定簇结合。CRD-BP影响RNA翻译，稳定性和定位，这取决于它所结合的RNA。在胎儿组织中大量表达但在出生后不久就受到抑制。因此，它可能在胎儿生命中有特殊的作用。三个发现也将CRD-BP与乳腺癌联系起来：（a）CRD-BP在正常乳腺组织中无法检测到，但在（B）CRD-BP基因在约30%的人乳腺肿瘤中扩增，（c）CRD-BP基因在约60%的人乳腺肿瘤中扩增，（d）CRD-BP基因在约30%的人乳腺肿瘤中扩增，（e）CRD-BP基因在约30%的人乳腺肿瘤中扩增。 CRD-BP在雌性转基因小鼠中诱导乳腺癌。三个目标使用转基因小鼠探讨这种RNA结合癌蛋白诱导乳腺肿瘤的途径。艾姆岛确定是否需要持续表达CRD-BP以维持现有乳腺癌肿瘤转基因小鼠中的乳腺肿瘤继续表达CRD-BP，因此可能是CRD-BP- 依赖于他们的生存。为了研究这一想法，Aim I利用了一种小鼠模型，其中乳腺- 特异性CRD-BP表达由四环素类似物强力霉素（dox）诱导。乳腺肿瘤是预期在dox处理的小鼠中出现。目的我然后问：这些肿瘤停止生长或退化时，撤回了吗我们的工作假设是，当CRD-BP表达受到抑制时，肿瘤会消退。 Aim II.应用基因芯片技术比较乳腺癌基因表达谱的差异组织和纯化的小鼠乳腺上皮细胞中表达或不表达CRD-BP。一些CRD- BP调控的RNA在乳腺肿瘤的诱导和维持中起着重要作用。 Aim III.确定遗传和环境因素如何促进乳腺肿瘤的发生， CRD-BP表达小鼠。目的是评估肿瘤抑制因子猿和化学物质致癌物N-乙基-N-亚硝基脲（ENU）影响CRD-BP介导的肿瘤形成。我们预测Apeficiency ENU治疗将与CRD-BP协同作用，增加肿瘤发病率和恶性度。许多研究充分的癌蛋白是转录因子或蛋白激酶。CRD-BP是一种这是一种不寻常的癌蛋白，因为它存在于细胞质中并与RNA结合。通过研究致癌的 CRD-BP的性质，它在体内影响的RNA，以及它与肿瘤诱导遗传和环境因素，我们希望发现新的肿瘤发生途径。