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: 8840893
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840893
• 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）：无法执行细胞周期停滞是癌症的一个标志。执行这些停滞的遗传和生化机制被称为检查点，并且由几种最常见的突变肿瘤抑制基因编码，如p53和p16 INK 4a。PTEN是人类癌症中最常见的失活肿瘤抑制基因之一。我们以前已经证明，PTEN在辐射诱导的细胞周期停滞期间在强制细胞大小停滞中起着核心作用。这种依赖于PTEN的细胞大小检查点的发现有助于解释PTEN突变的苍蝇和小鼠中存在显着增大的细胞，并提供了对遗传性PTEN突变导致错构瘤倾向的事实的见解，错构瘤的特征是增大的细胞。我们假设细胞大小检查点的丢失直接导致肿瘤发生。在该资助的第一个周期中，我们进行了许多与大小检查点直接相关的观察：（i）与癌细胞中通常有缺陷的其他检查点一样，PTEN依赖性细胞大小检查点可由电离辐射和DNA损伤性化疗药物诱导。(ii)PTEN依赖的细胞大小检查点是Akt不依赖的;（iii）细胞大小检查点控制需要PTEN依赖的肌动蛋白重塑;（iv）内源性PTEN在膜上与新型的PIP 2调节的肌动蛋白重塑复合物相互作用;（v）PTEN的突变失活导致p53的激活，表明大小检查点和G1/G2检查点之间存在串扰。第一次竞争性更新旨在建立在这些进展的基础上，以进一步评估人类细胞中PTEN依赖性大小检查点的机制基础和表型后果。在目标#1中，我们将确定细胞大小检查点控制是否需要PTEN调节肌动蛋白动力学。在目标#2中，我们提出鉴定含PTEN的肌动蛋白重塑复合物的组成和功能。在目标#3中，我们将确定细胞大小检查点控制的调节是否是PTEN介导的肿瘤抑制所需的。