Tumor-Inhibitory Effects of P1D1 in Gliomas

描述(由申请人提供)：本项目重点研究PID1(磷酸酪氨酸相互作用结构域包含1)在胶质瘤中的作用。PID1是2006年发现的一种含有磷酸酪氨酸结合(PTB)结构域的蛋白质，从未在癌症的背景下进行过研究。PID1的异位表达对不同细胞类型的增殖有相反的影响。利用微阵列和定量RT-PCR，我们发现PID1的高表达与两种类型的脑肿瘤--胶质瘤和髓母细胞瘤--的预后良好相关。我们的体外初步数据进一步表明，PID1的异位表达在三种不同类型的脑肿瘤中具有生长抑制作用：胶质母细胞瘤、髓母细胞瘤和不典型畸胎样横纹肌样肿瘤(ATRT)。我们选择将这一以PID1为中心的R21提案集中在胶质瘤上，因为它们构成了人类最常见的原发脑瘤，而且在恶性时预后很差。 这项建议的目的是揭示PID1在胶质瘤中介导其抑制作用的分子机制。具体地说，我们将测试PID1部分通过其PTB结构域在恶性胶质瘤中发挥抑制作用的假设。我们提出以下两个具体目标： 1)确定PID1在肾小管上皮细胞系中发挥抑制作用的关键结构域(S)。为了达到这个目的，我们将对PID1的已知和预测结构域进行突变，并测试它们抑制增殖和诱导细胞凋亡的能力。 2)检测PID1基因表达对NOD-SCID小鼠颅内人源性GBM肿瘤生长的影响。在这个目标中，我们将使用PID1的调控表达，并检测PID1表达对肿瘤生长、存活、增殖和凋亡的影响。 这项工作是新颖的，影响很大，因为它将进一步加深我们对PID1在胶质瘤中的分子机制和功能的了解，形成关于PID1在任何脑瘤和任何癌症中的知识的第一个基础。我们在初步数据中发现的临床相关性突出了这一主题的相关性和重要性。此外，我们在三种不同类型的脑瘤中发现了PID1的抑制功能，这表明PID1可能在其他癌症中也很重要，可能在其他疾病中也是如此，这可能会扩大我们工作的影响。

DESCRIPTION (provided by applicant): This project focuses on the role of PID1 (Phosphotyrosine Interaction Domain containing 1) in gliomas. PID1 is a phosphotyrosine binding (PTB) domain-containing protein that was discovered in 2006 and which has never been studied in the context of cancer. Ectopic expression of PID1 has opposite effects on proliferation in different cell types. Using microarrays and quantitative RT-PCR, we found that high expression of PID1 correlates with better outcome in two types of brain tumors, gliomas and medulloblastomas. Our in vitro preliminary data further show that ectopic expression of PID1 has growth-inhibitory effects in brain tumor cell lines from three different types of brain tumors: glioblastomas, medulloblastomas, and atypical teratoid rhabdoid tumors (ATRT). We chose to focus this PID1-centered R21 proposal on gliomas since they constitute the most common primary brain tumor in humans and have grim prognosis when malignant. The goal of this proposal is to uncover the molecular mechanisms by which PID1 mediates its inhibitory effect in gliomas. Specifically, we will test the hypothesis that PID1 exerts its inhibitory effect in malignant gliomas in part through its PTB domain. We propose the following two Specific Aims: 1) To determine the critical domain(s) of PID1 that mediate(s) its inhibitory function in GBM cell lines. In this Aim, we will make mutants of known and predicted domains of PID1 and test their ability to decrease proliferation and induce apoptosis. 2) To examine the effect of PID1 expression on growth of intracranial human cell line-derived GBM tumors in NOD-SCID mice. In this Aim, we will use regulated expression of PID1 and examine the effects of PID1 expression on tumor growth, survival, proliferation, and apoptosis. This work is novel and of high impact, as it will further our knowledge on the molecular mechanisms and functions of PID1 in gliomas, forming the first basis of knowledge about PID1 in any brain tumor and any cancer. The clinical correlation we uncovered in our Preliminary Data highlights the relevance and significance of this topic. In addition, our finding of an inhibitory function for PID1 in three different types of brain tumors suggest that PID1 may also be important in other cancers, and possibly in other diseases, potentially expanding the impact of our work.