The role of Phosphoinositide 3 Kinase isoforms in Prostate Cancer

磷脂酰肌醇3-激酶(PI3K)信号通路与人前列腺高度相关 癌症是在肿瘤抑制基因PTEN频繁丢失的基础上发展起来的疾病。PTEN 编码一种能降解PI3K脂类产物的磷酸酶，即磷脂酰肌醇-3，4，5-三磷酸 而PTEN的缺失会导致蛋白-丝氨酸/苏氨酸激酶AKT以及其他效应因子的过度激活 PI3K途径。在这个项目中，我们建议进一步阐明PI3K途径的组成部分 会导致前列腺癌。此外，我们建议操纵内源性PI3K和PTEN基因 并将PI3K的致癌突变引入小鼠体内，以检验PI3K的必要性和充分性 前列腺癌发生的亚型。这个项目有三个具体目标。目标1：我们将尝试 通过在人前列腺癌细胞系和异种移植模型中鉴定PI3K上游激活物 免疫沉淀PI3K并鉴定共沉淀蛋白。这项研究的结果应该会揭示 PI3K蛋白-酪氨酸激酶激活物，与前列腺癌有关，可作为靶向 治疗性干预。目的2：我们将PI3K的p110a亚单位的致癌突变引入到 通过转基因和敲击法获得前列腺组织，并确定这些突变的影响 关于前列腺癌和基因表达谱的研究。这项研究的结果将与我们的 先前PTEN缺失的结果和Sellers正在开发的小鼠模型的结果 实验室(项目2)和Sawyers实验室(项目3)，其中激活了组件的基因 PI3K途径的下游被引入前列腺。目标3：我们将推出一种药物- 可诱导的显性PI3K负性形式以确定急性抑制该通路的作用 由于PTEN缺失而发展的前列腺癌。此外，我们还将删除特定的催化基因和 前列腺特异性PTEN缺失与前列腺癌中IA类PI3K家族调节亚基的关系 以确定PI3K的哪些亚型对肿瘤的形成至关重要。这项研究的结果将 预测针对特定PI3K亚型的药物是否会有效治疗这种疾病。

The phosphoinositide 3-kinase (PI3K) signaling pathway has been highly implicated in human prostate cancer on the basis of frequent loss of the tumor suppressor gene, PTEN in advanced disease. PTEN encodes a phosphatase that hydrolyzes the lipid product of PI3K, phosphatidylinositol-3,4,5-trisphosphate and loss of PTEN results in hyperactivation of the protein-Ser/Thr kinase AKT as well as other effectors of the PI3K pathway. In this project, we propose to further elucidate components of the PI3K pathway that contribute to prostate cancer. In addition, we propose to manipulate endogenous PI3K and PTEN genes and introduce oncogenic mutations of PI3K into mice in order to test the necessity and sufficiency of PI3K isoforms for development of prostate cancer. This project has three specific aims. Aim 1: We will attempt to identify upstream activators of PI3K in human prostate cancer cell lines and in xenograph models by immunoprecipitating PI3K and identifying co-precipitating proteins. The results of this study should reveal protein-Tyr kinase activators of PI3K that contribute to prostate cancer and that could be targeted for therapeutic intervention. Aim 2: We will introduce oncogenic mutants of the p110a subunit of PI3K into prostate epithelial tissue by transgene and knockin approaches and determine the effect of these mutations on prostate neoplasia and on gene expression profiles. The results of this study will be compared to our previous results with PTEN deletions and with results from mouse models being developed in the Sellers' laboratory (Project 2) and Sawyers' laboratory (Project 3) where activated genes for components downstream of the PI3K pathway are being introduced into the prostate. Aim 3: We will introduce a drug- inducible dominant negative form of PI3K to determine the effect of acute inhibition of this pathway on prostate tumors that develop due to loss of PTEN. In addition, we will delete specific genes for catalytic and regulatory subunits of class IA PI3K family in the prostate in the context of prostate-specific PTEN deletion in order to determine which isoforms of PI3K are critical for tumor formation. The results of this study will predict whether drugs that target specific PI3K isoforms will be effective in treating this disease.