PTEN and Cancer

PTEN 与癌症

基本信息

批准号：
10686280
负责人：
Ramon E Parsons
金额：
$ 99.17万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-08-31
项目状态：
已结题

项目摘要

PTEN is one of the most frequently mutated tumor suppressors in human cancer, and effective approaches for treating cancer with PTEN alteration is needed. Inactivation of PTEN cooperates with different oncogenic signals to stimulate tumor initiation and progression and can be mutated in early or advanced human disease. Though two hit inactivation is more penetrant than one hit for PTEN in mice, partial inactivation via haploinsufficiency is sufficient to cause tumor progression. Much of PTEN’s tumor suppressor function can be attributed to its role as a negative regulator of PI3K signaling by virtue of its ability to act as a phosphatase that catalyzes the removal of the D-3 phosphate from phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 binds the PH domain of AKT kinase and the PH domains of two PIP3-regulated kinases PDK1 and mTORC2, which coordinately phosphorylate AKT to activate it. PIP3 in parallel binds the PH domains of PREX1 and PREX2 to stimulate GTP loading of RAC1. The parallel PIP3-dependent activation of AKT and RAC coordinate the activation of glycolysis in the cell, and under these conditions AKT activates mTORC1. Tumors that lack PTEN have elevated PIP3 with increased AKT, TORC1, and RAC signaling, increased DNA replication and up regulated metabolic pathways involved in cell growth. In normal physiology, PTEN is a key negative regulator of the insulin signaling pathway, and loss of PTEN leads to increased glucose uptake in different tissues of the body. Acute inactivation of PTEN in normal cells leads to increased cellular PIP3 and glucose flux accompanied by increased proliferation, migration, and survival. The PTEN locus encodes multiple isoforms of PTEN, including the recently identified PTEN-L, which share common phosphatase and C2 domains. My research program focuses on the PTEN tumor suppressor. In this proposal, the broad scientific question that I will ask is: what are the tumor suppressor functions of PTEN and PTEN-L and how are they regulated? The goals of this application are to define mechanisms of PTEN regulation, determine the consequences of inactivation in tissue and on cell proliferation and metabolism, and to develop approaches for targeting tumor cells based upon their PTEN status. I expect that greater understanding of PTEN’s inactivation and regulation will lead to improved therapy for cancer.

PTEN 是人类癌症中最常见突变的肿瘤抑制基因之一，是治疗癌症的有效方法治疗具有 PTEN 改变的癌症是必要的，PTEN 失活与不同的致癌基因协同作用。刺激肿瘤发生和进展的信号，并且可以在早期或晚期人类疾病中发生突变。尽管在小鼠中两次击中灭活比一次击中 PTEN 更具渗透性，但通过单倍体不足足以导致肿瘤进展。归因于其作为 PI3K 信号传导的负调节剂的作用，因为它能够充当磷酸酶，催化从磷脂酰肌醇-3,4,5-三磷酸 (PIP3) 上去除 D-3 磷酸盐。 AKT 激酶的 PH 结构域以及两个 PIP3 调节的激酶 PDK1 和 mTORC2 的 PH 结构域，协调磷酸化 AKT 以激活 PIP3，同时结合 PREX1 和 PREX2 的 PH 结构域。刺激 RAC1 的 GTP 负载 AKT 和 RAC 的并行 PIP3 依赖性激活协调细胞中糖酵解的激活，并且在这些条件下 AKT 激活肿瘤 PTEN 的 mTORC1。 PIP3 升高，AKT、TORC1 和 RAC 信号传导增加，DNA 复制增加等在正常生理学中，PTEN 是一个关键的负调节因子。胰岛素信号通路的缺失，PTEN 的缺失会导致不同组织的葡萄糖摄取增加正常细胞中 PTEN 的急性失活导致细胞 PIP3 和葡萄糖通量增加。伴随着增殖、迁移和存活的增加，PTEN 基因座编码多种亚型。 PTEN，包括最近发现的 PTEN-L，它们具有共同的磷酸酶和 C2 结构域。研究计划的重点是 PTEN 肿瘤抑制因子在这项提案中，我提出了广泛的科学问题。会问的是：PTEN和PTEN-L的抑癌功能是什么以及它们是如何调控的？本申请的目标是定义 PTEN 调节机制，确定以下结果：组织和细胞增殖和代谢失活，并开发针对肿瘤的方法我希望能够更好地了解 PTEN 的失活和调节。将改善癌症治疗。