Novel targets that are deregulated by loss of PTEN

PTEN 是一种肿瘤抑制因子，也是第一个被确定经常突变/缺失的磷酸酶 身体上的多种人类癌症。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 PIS 激酶信号传导的激活 途径。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。我们的研究将检验 PTEN 和 PIS 激酶/Akt 信号传导的新想法， 调节 RNA 聚合酶 (pol)III 依赖性基因表达，并且该调节事件在 PTEN 表达降低的人类癌细胞。作为 RNA pol III 产品、tRNA 和 5S rRNA，决定细胞的翻译能力，PTEN 可能抑制 RNA pol III 转录 是其抑制肿瘤功能的基础。我们的研究将确定 PTEN 的新靶点，以及 详细阐明 PTEN 缺失如何导致 RNA pol III 转录失调的机制 几种不同的人类细胞系。通过比较包含功能水平改变的细胞 PTEN，我们将：（1）确定PTEN是否抑制三大类RNA pol III的转录 发起人； (2)确定参与该反应的PTEN/Akt调节信号通路；和 确定 PTEN 是否也可以在细胞核中发挥作用，直接抑制转录过程。 (3) 识别 RNA pol III 转录机制因子的定量和/或定性变化 是 PTEN 的特定目标； (4) 确定转录成分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。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，并且 提供了第一个证据表明 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，这些通路和靶标在具有以下特征的细胞中受到异常调节： 失去 PTEN 功能，引起这些特定后果的基因表达，将提供有价值的 研究模拟 PTEN 功能的治疗药物的关系。

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.