Novel targets that are deregulated by loss of PTEN

由于 PTEN 缺失而解除管制的新靶标

• 批准号: 7045838
• 负责人: DEBORAH L. JOHNSON
• 金额: $ 23.12万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-06 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7045838
• 关键词: DNA directed RNA polymerase; biological signal transduction; cell line; chromatin immunoprecipitation; gene expression; genetic promoter element; genetic transcription; loss of heterozygosity; phosphatidylinositol 3 kinase; phosphomonoesterases; protein localization; protein structure function; proteomics; serine threonine protein kinase; tissue /cell culture; transcription factor; transcription termination; transfer RNA; tumor suppressor proteins

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，并且是第一种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的缺失促进人类癌症的发展。PTEN通常用于抑制PI 3激酶信号通路的活化。然而，关于在缺乏PTEN的细胞中丢失的PTEN介导的基因表达的变化知之甚少。我们的研究将检查新的想法，即PTEN和PI 3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表现出减少的PTEN表达的人癌细胞中丢失。由于RNA pol III产物tRNA和5S rRNA决定细胞的翻译能力，因此PTEN对RNA pol III转录的抑制可能是其肿瘤抑制功能的基础。我们的研究将确定新的靶点，并详细阐明，在几种不同的人类细胞系中，PTEN的丢失如何导致RNA pol III转录失调的机制。通过比较含有功能性PTEN水平改变的细胞，我们将：（1）确定PTEN是否抑制三种主要类型的RNA pol III启动子的转录;（2）确定参与这种反应的PTEN/Akt调节的信号通路;并确定PTEN是否也可以在细胞核中直接抑制转录过程。(3)鉴定PTEN特异性靶向的RNA pol III转录机制的因子的定量和/或定性变化;和（4）确定转录组分中的这些变化如何改变它们的功能和体内转录起始复合物的形成。从这些研究中，我们将确定新的下游靶点的PTEN是重要的，其功能作为一种肿瘤抑制剂，并提供第一个证据表明，RNA聚合酶III基因的失调是一个后果的损失的PTEN。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，导致这些特定的结果基因表达，这将为研究模拟PTEN功能的治疗剂提供有价值的联系。