PTEN and Cancer

PTEN 与癌症

• 批准号: 10227679
• 负责人: Ramon E Parsons
• 金额: $ 101.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10227679
• 关键词: Acute; Binding; C2 Domain; Cancer Patient; Cell Proliferation; Cells; Cellular Metabolic Process; DNA biosynthesis; Excision; Glucose; Glycolysis; Goals; Growth; Guanosine Triphosphate; Human; Insulin Signaling Pathway; Malignant Neoplasms; Metabolic Pathway; Mus; Mutate; Normal Cell; Oncogenic; PDPK1 gene; PH Domain; PTEN gene; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiology; Protein Isoforms; Proto-Oncogene Proteins c-akt; Regulation; Research; Role; Signal Transduction; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cancer cell; cancer therapy; cell growth; glucose uptake; human disease; improved; insight; migration; neoplastic cell; phosphatidylinositol 3-phosphate; programs; tumor; tumor initiation; tumor progression

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是人类肿瘤中最常突变的肿瘤抑制因子之一，并且是治疗肿瘤的有效方法。 需要用PTEN改变来治疗癌症。抑癌基因PTEN的失活与不同的致癌基因协同作用 信号来刺激肿瘤的发生和发展，并且可以在早期或晚期人类疾病中突变。 虽然在小鼠中两次打击失活比一次打击对PTEN的渗透性更强，但通过 单倍不足足以引起肿瘤进展。PTEN的大部分肿瘤抑制功能可能是 这归因于其作为PI 3 K信号传导负调节剂的作用，这是由于其作为磷酸酶的能力， 催化从磷脂酰肌醇-3，4，5-三磷酸（PIP 3）中除去D-3磷酸。PIP 3结合 AKT激酶的PH结构域和两种PIP 3调节的激酶PDK 1和mTORC 2的PH结构域， PIP 3平行结合PREX 1和PREX 2的PH结构域， 刺激RAC 1 GTP负载。AKT和RAC的并行PIP 3依赖性激活协调了细胞的免疫反应。 在细胞中糖酵解的激活，并且在这些条件下AKT激活mTORC 1。缺乏PTEN的肿瘤 PIP 3升高，AKT、TORC 1和RAC信号增加，DNA复制增加， 参与细胞生长的调节代谢途径。在正常生理学中，PTEN是一个关键的负调节因子， 在胰岛素信号通路中，PTEN的缺失导致不同组织的葡萄糖摄取增加。 身体正常细胞中PTEN的急性失活导致细胞PIP 3和葡萄糖通量增加 伴随着增加的增殖、迁移和存活。PTEN基因座编码多个异构体， PTEN，包括最近鉴定的PTEN-L，其共享共同的磷酸酶和C2结构域。我 研究计划的重点是PTEN肿瘤抑制因子。在这个提议中，我提出的广泛的科学问题， 我想问的是：PTEN和PTEN-L的肿瘤抑制功能是什么，它们是如何调节的？的 本申请的目的是定义PTEN调节的机制，确定 在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 根据其PTEN状态。我希望对PTEN的失活和调控有更深入的了解 将改善癌症治疗。