A PTEN-dependent cell size checkpoint in human cells

人类细胞中 PTEN 依赖性细胞大小检查点

• 批准号: 8578465
• 负责人: TODD A WALDMAN
• 金额: $ 24.12万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-11 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578465
• 关键词: Actins; Animal Model; Biochemical; Biological Models; CDKN2A gene; Cell Cycle Arrest; Cell Size; Cells; Complex; DNA Damage; Data; Defect; Endometrial Carcinoma; Gelsolin; Genetic; Glioblastoma; Grant; Hamartoma; Human; In Vitro; Inherited; Ionizing radiation; Malignant Neoplasms; Mediating; Membrane; Methods; Mus; Mutate; Mutation; Normal Cell; PTEN gene; Pharmaceutical Preparations; Phosphatidylinositol 4,5-Diphosphate; Phosphorylation; Play; Predisposition; Prostate Adenocarcinoma; Proteins; Radiation; Regulation; Regulation of Cell Size; Role; Tertiary Protein Structure; Testing; Tumor Suppression; Tumor Suppressor Genes; anti-cancer therapeutic; base; cancer cell; design; fly; in vivo Model; insight; melanoma; mutant; neoplastic cell; novel; polymerization; public health relevance; research study; tensin; therapeutic target; tool; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The inability to enforce cell cycle arrests is one hallmark of cancer. The genetic and biochemical mechanisms that enforce these arrests are known as checkpoints, and are encoded by several of the most commonly mutated tumor suppressor genes such as p53 and p16INK4a. PTEN is one of the most commonly inactivated tumor suppressor genes in human cancer. We have previously demonstrated that PTEN plays a central role in enforcing cell size arrest during radiation-induced cell cycle arrest. The discover of this PTEN-dependent cell size checkpoint helped to explain the existence of dramatically enlarged cells in PTEN mutant flies and mice, and provided insight into the fact that inherited PTEN mutations cause a predisposition to hamartomas, which are characterized by enlarged cells. We hypothesize that loss of the cell size checkpoint contributes directly to tumorigenesis. In the first cycle of this grant, we made a number of observations directly related to the size checkpoint: (i) Like other checkpoints that are commonly defective in cancer cells, the PTEN- dependent cell size checkpoint is inducible by ionizing radiation and DNA-damaging chemotherapeutic drugs. (ii) The PTEN-dependent cell size checkpoint is Akt-independent; (iii) PTEN-dependent actin remodeling is required for cell size checkpoint control; (iv) Endogenous PTEN interacts at the membrane with a novel, PIP2-regulated actin remodeling complex; (v) Mutational inactivation of PTEN leads to activation of p53, suggesting the existence of crosstalk between the size checkpoint and the G1/G2 checkpoints. This first competitive renewal is designed to build on these advances to further evaluate the mechanistic basis and phenotypic consequences of the PTEN-dependent size checkpoint in human cells. In Aim #1 we will determine if regulation of actin dynamics by PTEN is required for cell size checkpoint control. In Aim #2 we propose to identify the composition and function of a PTEN-containing actin remodeling complex. In Aim #3 we will determine if regulation of cell size checkpoint control is required for PTEN-mediated tumor suppression.

描述（由申请人提供）：无法实施细胞周期阻滞是癌症的一个标志。执行这些捕获的遗传和生化机制被称为检查点，由几种最常见的突变肿瘤抑制基因（如p53和p16INK4a）编码。PTEN是人类肿瘤中最常见的灭活肿瘤抑制基因之一。我们之前已经证明，在辐射诱导的细胞周期阻滞中，PTEN在加强细胞大小阻滞中起着核心作用。这种PTEN依赖性细胞大小检查点的发现有助于解释PTEN突变果蝇和小鼠中细胞急剧增大的存在，并提供了关于遗传PTEN突变导致错构瘤易感性的事实的见解，错构瘤的特征是细胞增大。我们假设细胞大小检查点的缺失直接导致了肿瘤的发生。在该资助的第一个周期中，我们进行了一些与大小检查点直接相关的观察：(i)与癌细胞中通常存在缺陷的其他检查点一样，依赖PTEN的细胞大小检查点可通过电离辐射和dna损伤化疗药物诱导。（ii） pten依赖性细胞大小检查点与akt无关；（iii）细胞大小检查点控制需要依赖pten的肌动蛋白重塑；（iv）内源性PTEN在细胞膜上与一种新的、pip2调控的肌动蛋白重塑复合体相互作用；(v) PTEN突变失活导致p53激活，提示大小检查点和G1/G2检查点之间存在串扰。这是第一次竞争性更新，旨在建立在这些进展的基础上，进一步评估pten依赖性大小检查点在人类细胞中的机制基础和表型后果。在目标1中，我们将确定是否需要通过PTEN调节肌动蛋白动力学来控制细胞大小检查点。在目标#2中，我们建议鉴定含有pten的肌动蛋白重塑复合体的组成和功能。在Aim #3中，我们将确定pten介导的肿瘤抑制是否需要调节细胞大小检查点控制。