Novel targets that are deregulated by loss of PTEN

PTEN是一种肿瘤抑制因子，是第一个被发现频繁突变/缺失的磷酸酶 在各种人类癌症的躯体上。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激酶信号的激活 路径。然而，关于PTEN介导的基因表达的变化还知之甚少，这种变化在 缺乏PTEN的细胞。我们的研究将检验PTEN和PIS激酶/Akt信号转导的新想法， 调节RNA聚合酶(PolI)病态依赖的基因表达，这一调节事件在 表现出PTEN表达降低的人类癌细胞。作为RNA polIII产物，tRNAs和5S RRNAs决定细胞的翻译能力，PTEN可能抑制RNA polIII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，以及 详细阐明PTEN基因缺失导致RNAPolIII转录失控的机制。 几种不同的人类细胞系。通过比较包含功能水平变化的细胞 PTEN，我们将：(1)确定PTEN是否抑制三大类RNA polIII的转录 启动子；(2)确定参与这种反应的PTEN/Akt调节的信号通路；以及 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RNAPolIII转录机制中因子(S)的数量和/或质量变化 是/被PTEN特异性靶向；以及(4)确定这些转录成分的变化是如何 在体内改变它们的功能和转录起始复合体的形成。从这些研究中，我们发现 将确定新的PTEN下游靶点，这些靶点对其作为肿瘤抑制因子和 提供了第一个证据，证明RNAPolIII基因的解除调控是PTEN缺失的结果。 确定PTEN介导的信号通路和靶点在具有 PTEN功能缺失，引起这些特定后果的基因表达，将提供有价值的 Nexus用于研究模拟PTEN功能的治疗剂。

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.