PTEN and Cancer

PTEN 与癌症

• 批准号: 9759839
• 负责人: Ramon E Parsons
• 金额: $ 98.16万
• 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/9759839
• 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是人类癌症中最常见的突变肿瘤补充剂之一，有效的方法 需要通过PTEN改变治疗癌症。 PTEN与不同的致癌性合作的灭活 刺激肿瘤开始和进展的信号，可以在早期或晚期人类疾病中突变。 尽管两次失活的两次失活比在小鼠中对PTEN的击中更为渗透，但部分失活通过 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 归因于其作为PI3K信号的负调节剂的作用，因为它的能力充当磷酸酶 催化从磷脂酰肌醇-3,4,5-三磷酸（PIP3）中去除D-3磷酸盐。 PIP3结合 Akt激酶的pH结构域以及两个PIP3调节激酶PDK1和MTORC2的pH结构域，它们 协调磷酸化Akt激活它。并行的PIP3结合prex1和prex2的pH结构域与 刺激Rac1的GTP加载。 AKT和RAC坐标的平行PIP3依赖性激活 细胞中糖酵解的激活，在这些条件下AKT激活MTORC1。缺乏PTEN的肿瘤 随着AKT，TORC1和RAC信号的增加，PIP3升高，DNA复制增加并向上增加 调节的代谢途径参与细胞生长。在正常生理学中，PTEN是关键的负调节剂 胰岛素信号通路和PTEN的丧失导致在不同时机中葡萄糖的吸收增加 身体。正常细胞中PTEN的急性失活导致细胞PIP3和葡萄糖通量增加 伴随着增殖，迁移和生存的增加。 PTEN基因座编码多种同工型 PTEN，包括最近鉴定出的PTEN-L，共有常见的磷酸酶和C2结构域。我的 研究计划的重点是抑制PTEN肿瘤。在这一提议中，我的广泛科学问题是 会问是：PTEN和PTEN-L的肿瘤抑制功能是什么？它们如何调节？这 该应用的目标是定义PTEN监管的机制，确定的后果 在组织，细胞增殖和代谢中失活，并开发靶向肿瘤的方法 细胞基于其PTEN状态。我希望对PTEN的失活和监管有更深入的了解 将导致改善癌症治疗。