Novel targets that are deregulated by loss of PTEN

由于 PTEN 缺失而解除管制的新靶标

基本信息

批准号：
7176233
负责人：
DEBORAH L. JOHNSON
金额：
$ 22.47万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2006-02-06 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7176233
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Antibodies Apoptosis Biological Assay Cell Cycle Cell Nucleus Cells Class Complex Condition DNA-Directed RNA Polymerase DNA-Protein Interaction Data Dominant-Negative Mutation Electron Transport Complex III Event Exhibits Gap Junctions Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Human Human Cell Line Human Development In Vitro Investigation Lead Malignant Epithelial Cell Malignant Neoplasms Mediating Molecular Mutate Nexus (resin cement)Nuclear Oncogene Deregulation PTEN gene Pathway interactions Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphoric Monoester Hydrolases Polymerase Proteins RNA Interference Pathway RNA Polymerase III RNA Polymerase III Transcription Pathway Rate Repression Reverse Transcriptase Polymerase Chain Reaction Ribosomal Protein S6 Kinase Ribosomal RNA Running Signal Pathway Signal Transduction Signaling Molecule Structure Testing Therapeutic Agents Transcription Factor TFIIIB Transcription Initiation Transcription Process Transcriptional Regulation Transfer RNA Tumor Suppressor Proteins U6 small nuclear RNA Untranslated RNA Work cell growth cellular targeting chromatin immunoprecipitation design gene repression human FRAP1 protein in vivo inhibitor/antagonist mutant novel novel therapeutics polypeptide promoter reconstitution response transcription factor transcription factor TFIIIC tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): PTEN is a tumor suppressor and the first phosphatase identified to be frequently mutated/deleted somatically in a variety of human cancers. Substantial evidence supports that loss of PTEN promotes the development of human cancer. PTEN normally serves to repress the activation of the PI3 kinase signaling pathway. However, little is yet known regarding PTEN-mediated changes in gene expression that are lost in cells that lack PTEN. Our studies will examine the novel idea that PTEN, and PI3 kinase/Akt signaling, regulates RNA polymerase (pol) Ill-dependent gene expression and that this regulatory event is lost in human carcinoma cells that exhibit reduced PTEN expression. As RNA pol III products, tRNAs and 5S rRNAs, determine the translational capacity of cells, repression of RNA pol III transcription by PTEN is likely to be fundamental to its tumor suppressing function. Our studies will identify new targets of PTEN, and elucidate in detail, the mechanism for how loss of PTEN leads to deregulation of RNA pol III transcription in several different human cell lines. By comparing cells that contain alterations in the levels of functional PTEN, we will: (1) Determine whether PTEN represses transcription of the three major classes of RNA pol III promoters; (2) Determine the PTEN/Akt-regulated signaling pathways involved in this response; and determine whether PTEN may also function in the nucleus to directly repress the transcription process. (3) Identify quantitative and/or qualitative changes in factor(s) of the RNA pol III transcription machinery that is/are specifically targeted by PTEN; and (4) Determine how these changes in the transcription components alters their function and the formation of transcription initiation complexes in vivo. From these studies, we will identify novel downstream targets of PTEN that are important for its function as a tumor suppressor and provide the first evidence that the deregulation of RNA pol III genes is a consequence of the loss of PTEN. Defining the PTEN-mediated signaling pathways and targets that are aberrantly regulated in cells that have lost PTEN function, giving rise to these specific consequences gene expression, will provide a valuable nexus for investigation of therapeutic agents that mimic PTEN function.

描述（由申请人提供）：PTEN 是一种肿瘤抑制因子，也是第一个被鉴定为在多种人类癌症中体细胞频繁突变/缺失的磷酸酶。大量证据支持 PTEN 的缺失会促进人类癌症的发展。 PTEN 通常用于抑制 PI3 激酶信号通路的激活。然而，对于 PTEN 介导的基因表达变化知之甚少，而这些变化在缺乏 PTEN 的细胞中会丢失。我们的研究将检验以下新观点：PTEN 和 PI3 激酶/Akt 信号传导调节 RNA 聚合酶 (pol) III 依赖性基因表达，并且这种调节事件在表现出 PTEN 表达降低的人类癌细胞中丢失。由于 RNA pol III 产物、tRNA 和 5S rRNA 决定细胞的翻译能力，PTEN 对 RNA pol III 转录的抑制可能是其肿瘤抑制功能的基础。我们的研究将确定 PTEN 的新靶点，并详细阐明 PTEN 缺失如何导致几种不同人类细胞系中 RNA pol III 转录失调的机制。通过比较功能性 PTEN 水平发生变化的细胞，我们将： (1) 确定 PTEN 是否抑制三大类 RNA pol III 启动子的转录； (2)确定参与该反应的PTEN/Akt调节信号通路；并确定 PTEN 是否也可能在细胞核中发挥作用，直接抑制转录过程。 (3) 鉴定 PTEN 特异性靶向的 RNA pol III 转录机制因子的数量和/或质变； (4)确定转录成分的这些变化如何改变它们的功能以及体内转录起始复合物的形成。从这些研究中，我们将确定 PTEN 的新下游靶点，这些靶点对其作为肿瘤抑制因子的功能非常重要，并提供第一个证据，证明 RNA pol III 基因的失调是 PTEN 缺失的结果。定义 PTEN 介导的信号通路和靶点，这些通路和靶点在失去 PTEN 功能的细胞中受到异常调节，从而产生这些特定的基因表达结果，将为研究模拟 PTEN 功能的治疗药物提供有价值的联系。