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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的突变肿瘤抑制基因之一，是治疗肿瘤的有效方法用PTEN改变治疗癌症是必要的。PTEN失活与不同致癌基因的协同作用刺激肿瘤启动和进展的信号，在早期或晚期人类疾病中可能发生突变。虽然在小鼠中，两次打击对PTEN的失活比一次打击更具穿透性，但通过单倍体功能不全就足以导致肿瘤进展。PTEN的大部分肿瘤抑制功能可以是归因于它作为PI3K信号的负调节因子的作用，因为它能够作为一种磷酸酶催化从磷脂酰肌醇-3，4，5-三磷酸(PIP3)中脱除D-3磷酸。PIP3结合 AKT激酶的PH结构域和PIP3调节的两个激酶PDK1和mTORC2的PH结构域，它们协同磷酸化AKT以激活它。PIP3平行结合PREX1和PREX2的PH结构域刺激RAC1的GTP负荷。AKT和RAC的并行依赖于PIP3的激活协调激活细胞中的糖酵解，在这些条件下，AKT激活mTORC1。缺乏PTEN的肿瘤提高了PIP3，增加了AKT、TORC1和RAC信号，增加了DNA复制和UP 参与细胞生长的调节代谢途径。在正常生理学中，PTEN是一个关键的负性调节因子在胰岛素信号通路中，PTEN的缺失导致不同组织对葡萄糖的摄取增加。尸体。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而来的是更多的增殖、迁移和存活。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。我的研究计划的重点是PTEN肿瘤抑制因子。在这项提议中，我提出的广泛的科学问题会问的是：PTEN和PTEN-L的抑癌功能是什么？它们是如何调节的？这个本申请的目标是定义PTEN调节的机制，确定组织中的失活以及对细胞增殖和代谢的影响，并开发靶向肿瘤的方法基于其PTEN状态的细胞。我希望更多地了解PTEN的失活和调节将导致癌症治疗的改进。