PTEN Tumor Suppressor and Signal Transduction

描述（由申请人提供）：PTEN是一种肿瘤抑制因子，其在大量人类癌症中失调以激活致癌性磷酸肌醇-3激酶（PI 3 K）途径。PTEN的失活导致多种表型，包括癌症、干细胞生物学变化和基本过程如增殖和凋亡的改变。我们最近确定PI 3 K途径激活转录抑制因子NFIL 3/E4 BP 4。NFIL 3在缺乏PTEN的人乳腺癌中过表达。此外，在多种类型的预后不良癌症中观察到NFIL 3的过度表达。我们已经表明，NFIL 3结合并招募HDAC 2启动子去乙酰化组蛋白和沉默基因，甚至在多个FOXO靶基因上抑制最近识别的核FOXO蛋白库。我们的研究结果具有广泛的意义，表明NFIL 3抑制许多非FOXO靶点，可以介导PTEN突变导致的染色质重编程。本申请将使用生物化学、信号转导、小鼠遗传学和癌细胞生物学的组合来解决以下目标：1）理解NFIL 3改变靶基因的表观遗传调控的机制，2）确定NFIL 3对基因表达变化和由基因切除PTEN引起的染色质修饰的贡献，3）证明NFIL 3对小鼠和细胞中由于PTEN突变引起的肿瘤和其他表型的贡献，和4）定义NFIL 3如何受PTEN调节及其对基于PI 3 K的癌症治疗的意义。 公共卫生相关性：对人类肿瘤的分析表明，PI 3 K途径是许多形式的恶性肿瘤中最频繁激活的途径之一。在这里，我们将定义PI 3 K调节NFIL 3的重要机制，其似乎负责以PI 3 K依赖性方式调节染色质。这项工作对癌症和干细胞生物学具有重要意义。

DESCRIPTION (provided by applicant): PTEN is a tumor suppressor that is deregulated in a large number of human cancers to activate the oncogenic phosphoinositide-3 kinase (PI3K) pathway. Inactivation of PTEN leads to multiple phenotypes including cancer, changes in stem cell biology and alteration of fundamental processes such as proliferation and apoptosis. We have recently determined that the PI3K pathway activates the transcriptional repressor NFIL3/E4BP4. NFIL3 is over expressed in human breast cancers lacking PTEN. Moreover, over expression of NFIL3 is seen in multiple types of poor-prognosis cancer. We have shown that NFIL3 binds and recruits HDAC2 to promoters to deacetylate histones and silence genes and even represses a recently recognized pool of nuclear FOXO proteins at multiple FOXO target genes. Our findings have broad implications that suggest that NFIL3, which represses numerous non-FOXO targets, could mediate reprogramming of chromatin as a consequence of PTEN mutation. This application will use a combination of biochemistry, signal transduction, mouse genetics, and cancer cell biology to address the following goals 1) to understand the mechanism by which NFIL3 alters the epigenetic regulation of target genes, 2) to determine the contribution of NFIL3 to changes in gene expression and chromatin modification caused by genetic ablation of PTEN, 3) to demonstrate the contribution of NFIL3 to tumor and other phenotypes due to PTEN mutation in mice and cells, and 4) to define how NFIL3 is regulated by PTEN and its implication for PI3K- based cancer therapy. PUBLIC HEALTH RELEVANCE: Analysis of human tumors has shown that the PI3K pathway is one of the most frequently activated pathways in many forms of malignancy. Here we will define an important mechanism of PI3K regulation of NFIL3 that appears to be responsible for modulating chromatin in a PI3K- dependent manner. This work has important implications for cancer and stem cell biology.