Novel targets that are deregulated by loss of PTEN

描述(申请人提供)：PTEN是一种肿瘤抑制因子，也是在多种人类癌症中发现的第一种经常发生体细胞突变/缺失的磷酸酶。大量证据支持PTEN基因的缺失促进了人类癌症的发展。PTEN通常用于抑制PI3信号通路的激活。然而，关于PTEN介导的基因表达的变化在缺乏PTEN的细胞中丢失的情况还知之甚少。我们的研究将检验这一新的想法，即PTEN和PI3激酶/Akt信号，调节RNA聚合酶(PolIll)依赖的基因表达，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。作为RNA polIII的产物，tRNAs和5S rRNAs决定了细胞的翻译能力，PTEN对RNA polIII转录的抑制可能是其肿瘤抑制功能的基础。我们的研究将发现PTEN的新靶点，并详细阐明PTEN的缺失如何导致几种不同的人类细胞系中RNA PolIII转录的失控。通过比较含有功能PTEN水平变化的细胞，我们将：(1)确定PTEN是否抑制三大类RNA polIII启动子的转录；(2)确定参与这一反应的PTEN/Akt调节的信号通路；以及确定PTEN是否也可能在细胞核中直接抑制转录过程。(3)确定PTEN特异性靶向的RNAPolIII转录机制因子(S)的数量和/或质量变化；以及(4)确定这些转录成分的这些变化如何改变其功能和体内转录起始复合体的形成。从这些研究中，我们将发现新的PTEN下游靶点，这些靶点对其作为肿瘤抑制因子的功能是重要的，并提供第一个证据，证明RNA PolIII基因的解除调控是PTEN缺失的结果。明确PTEN介导的信号通路和靶点在失去PTEN功能的细胞中被异常调控，从而导致这些特定的结果基因表达，将为研究模拟PTEN功能的治疗药物提供有价值的联系。

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.