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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：
7749054
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 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7749054
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Antibodies Apoptosis Biological Assay Cell Cycle Cell Nucleus Cells Complex 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 Nuclear Oncogene Deregulation PTEN gene Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Polymerase Proteins RNA Polymerase III 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

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 PIS 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 PIS 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.

PTEN是一种肿瘤抑制因子，也是第一个被鉴定为频繁突变/缺失的磷酸酶在多种人类癌症的体细胞中。大量证据支持PTEN的缺失促进了人类癌症的发展。PTEN通常用于抑制PIS激酶信号传导的活化通路然而，关于PTEN介导的基因表达变化，缺乏PTEN的细胞我们的研究将检验新的想法，即PTEN和PIS激酶/Akt信号传导，调节RNA聚合酶（pol）III依赖的基因表达，并且这种调节事件在显示出降低的PTEN表达的人癌细胞。作为RNA pol III产物，tRNA和5S rRNA决定了细胞的翻译能力，PTEN可能抑制RNA聚合酶III的转录是其肿瘤抑制功能的基础。我们的研究将确定PTEN的新靶点，详细阐明了PTEN的缺失如何导致RNA聚合酶III转录失调的机制，几种不同的人类细胞系通过比较细胞中含有功能水平的改变，我们将：（1）确定PTEN是否抑制三种主要类型的RNA聚合酶III的转录（2）确定参与该应答的PTEN/Akt调节的信号传导途径;和确定PTEN是否也可以在细胞核中直接抑制转录过程。（三）确定RNA pol III转录机制因子的定量和/或定性变化，是/是由PTEN特异性靶向的;和（4）确定转录组分中的这些变化是如何发生的。改变它们的功能和体内转录起始复合物的形成。通过这些研究，我们将确定新的下游目标的PTEN是重要的功能，作为一种肿瘤抑制剂，提供了RNA pol III基因失调是PTEN丢失的结果的第一个证据。定义在具有以下特征的细胞中异常调节的PTEN介导的信号传导途径和靶点：失去PTEN功能，引起这些特定后果的基因表达，将提供一个有价值的研究模拟PTEN功能的治疗剂的关系。