Role of PTEN in Mitosis and Chromosome Stability

PTEN 在有丝分裂和染色体稳定性中的作用

• 批准号: 8413851
• 负责人: WEN H. SHEN
• 金额: $ 30.33万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413851
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Aneuploidy; Automobile Driving; Biological Markers; Cell Nucleus; Cell division; Cell physiology; Cells; Chromosomal Instability; Chromosomal Stability; Chromosome Segregation; Chromosomes; Cytoplasm; Data; Defect; Detection; Development; Drug resistance; Ensure; Equilibrium; Evolution; Exhibits; Experimental Leukemia; Functional disorder; Future; Genes; Genetic; Genetic Materials; Genetic Processes; Genome; Genome Stability; Genomic Instability; Genomics; Germ-Line Mutation; Goals; Human; Karyotype; Knock-out; Lead; Link; Lipids; Maintenance; Malignant Neoplasms; Mitosis; Mitotic; Mitotic Chromosome; Molecular and Cellular Biology; Multiple Hamartoma Syndrome; Mus; Mutate; Mutation; Nuclear; Numerical Chromosomal Abnormality; Oncogenic; Outcome; PTEN gene; PTEN protein; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Polyploidy; Process; Protein phosphatase; Proteins; Regulation; Research; Research Project Grants; Resistance; Role; Signal Pathway; Signal Transduction; Structural Chromosomal Abnormality; Testing; Tissues; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; driving force; human PLK1 protein; insight; lymphoblastoid cell line; novel; polo-like kinase kinase 1; prevent; therapeutic development; transmission process; tumor; tumorigenesis

DESCRIPTION (provided by applicant): PTEN is one of the most frequently mutated genes in human cancer and the PTEN protein is considered to be a "guardian of the genome" because of its important role in protecting chromosomal integrity. Observation of structural chromosome aberrations and aneuploidy in cells and tissues lacking functional PTEN brings the link between PTEN and chromosome stability sharply into focus. In our recent studies, we found that cells lacking PTEN exhibit chromosome missegregation and prominent polyploidy, suggesting that PTEN functions during mitosis to control genomic and karyotypic stability. Chromosome instability acquired during aberrant mitosis plays a causative role in tumor development and progression. The long-term goal of this research project is to establish the novel concept that PTEN plays an essential part in controlling mitotic chromosome stability and that its function in maintaining mitotic fidelity is a major driving force in tumor suppression. In support of this aim, our exciting new preliminary data reveal that PTEN deficiency leads to gross genomic alterations manifested by polyploidization and confers cellular resistance to spindle perturbation. Significantly, we found that the protein phosphatase activity of PTEN is required for maintenance of a normal karyotype, and for cellular sensitivity to spindle drugs. In addition, our data have revealed that a key mitotic kinase, polo-like kinase 1 (Plk1), is a potential PTEN target. These findings lead to our hypothesis that PTEN is required for ensuring faithful chromosome inheritance during mitosis and that the protein phosphatase function of PTEN is critical for restraining aberrant mitotic kinase activity in order to maintain a normal karyotype. To test this hypothesis, we propose two specific aims as follows. In Aim 1, we will demonstrate mitotic chromosome instability is a prevailing phenotypic consequence of PTEN deficiency. We will use a Pten conditional knockout leukemia animal model and a panel of Cowden syndrome-derived human lymphoblastoid cell lines to validate the potential causative relationship between PTEN deficiency and karyotypic alterations. In Aim 2, we will define the inhibitory signaling link between PTEN and Plk1 and elucidate the mechanism by which their balanced interplay contributes to karyotypic fidelity and tumor suppression. Using cellular and molecular biology approaches, we will characterize PTEN as an essential mitotic phosphatase and demonstrate that Plk1 is a protein target of the PTEN phosphatase that maintains mitotic chromosome stability. Successful completion of these aims will provide insight into the mechanisms whereby PTEN deficiency triggers mitotic defects and chromosomal instability, and thus leads to tumorigenesis. New findings from this project will offer a new perspective for further mechanistic studies and future development of therapeutic strategies in treating human cancers.

描述（由申请人提供）：PTEN是人类癌症中最常见的突变基因之一，PTEN蛋白被认为是“基因组的监护人”，因为它在保护染色体完整性中的重要作用。在缺乏功能性PTEN的细胞和组织中观察到结构性染色体畸变和非整倍性，使PTEN与染色体稳定性之间的联系急剧成为焦点。在我们最近的研究中，我们发现缺乏PTEN的细胞表现出染色体的错误分析和突出的多倍体，这表明PTEN在有丝分裂过程中的功能以控制基因组和核型稳定性。在异常有丝分裂期间获得的染色体不稳定性在肿瘤发育和进展中起致病作用。该研究项目的长期目标是建立一个新的概念，即PTEN在控制有丝分裂染色体稳定性中起着至关重要的作用，并且其在维持有丝分裂保真度中的功能是肿瘤抑制中的主要驱动力。为了支持这一目标，我们令人兴奋的新初步数据表明，PTEN缺乏症会导致多倍体化表现出的基因组变化，并赋予细胞抗螺旋扰动的抗性。值得注意的是，我们发现PTEN的蛋白质磷酸酶活性是维持正常核型和细胞对纺锤体药物的敏感性所必需的。此外，我们的数据表明，关键的有丝分裂激酶类似polo样激酶1（PLK1）是潜在的PTEN靶标。这些发现导致了我们的假设，即确保有丝分裂过程中忠实的染色体遗传需要PTEN，并且PTEN的蛋白质磷酸酶功能对于限制异常有丝分裂激酶活性以维持正常的核型至关重要。为了检验这一假设，我们提出了两个具体目标，如下所示。在AIM 1中，我们将证明有丝分裂染色体不稳定性是PTEN缺乏症的主要表型后果。我们将使用PTEN条件敲除白血病模型和Cowden综合征衍生的人淋巴细胞细胞系的面板来验证PTEN缺乏症与核型改变之间的潜在因果关系。在AIM 2中，我们将定义PTEN和PLK1之间的抑制性信号连接，并阐明其平衡相互作用有助于核型保真度和肿瘤抑制的机制。使用细胞和分子生物学方法，我们将PTEN将PTEN表征为必不可少的有丝分裂磷酸酶，并证明PLK1是维持有丝分裂染色体稳定性的PTEN磷酸酶的蛋白质靶标。这些目标的成功完成将提供有关PTEN缺乏症触发有丝分裂缺陷和染色体不稳定性的机制的洞察力，从而导致肿瘤发生。该项目的新发现将为治疗人类癌症的治疗策略提供进一步的机械研究和未来发展的新观点。