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: 9000703
• 负责人: WEN H. SHEN
• 金额: $ 28.2万
• 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/9000703
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Aneuploidy; Automobile Driving; Cell Nucleus; Cell division; Cell physiology; Cells; Chromosomal Instability; Chromosomal Stability; Chromosome Segregation; Chromosomes; Cytoplasm; DNA Sequence Alteration; Data; Defect; Detection; Development; Ensure; Equilibrium; Evolution; Exhibits; Experimental Leukemia; Functional disorder; Future; Genes; Genetic; Genetic Materials; Genetic Processes; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Human; Karyotype; Knock-out; Lead; Link; Lipids; Maintenance; Malignant Neoplasms; Mitosis; Mitotic; Mitotic Chromosome; Molecular and Cellular Biology; Mus; Mutate; Mutation; Nuclear; Numerical Chromosomal Abnormality; Oncogenic; Outcome; PLK1 gene; 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 Markers; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; driving force; insight; mouse model; novel; polo-like kinase kinase 1; prevent; therapeutic development; transmission process; tumor; tumorigenesis

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 Pten phosphatase-deficient mouse model 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.

PTEN是人类癌症中最频繁突变的基因之一，并且PTEN蛋白被认为是 由于其在保护染色体完整性方面的重要作用，被称为“基因组的监护人”。观察 在缺乏功能性PTEN的细胞和组织中，结构性染色体畸变和非整倍性 PTEN和染色体稳定性之间的关系成为焦点。在我们最近的研究中，我们发现细胞缺乏 PTEN表现出染色体错误分离和突出的多倍性，表明PTEN在细胞周期中起作用。 有丝分裂以控制基因组和核型稳定性。异常有丝分裂中获得的染色体不稳定性 在肿瘤的发生和发展中起着致病作用。该研究项目的长期目标是 建立了新的概念，即PTEN在控制有丝分裂染色体稳定性中起重要作用， 其维持有丝分裂保真度的功能是肿瘤抑制的主要驱动力。为支持这一 目的是，我们令人兴奋的新的初步数据表明，PTEN缺陷导致总的基因组改变， 表现为多倍化并赋予细胞对纺锤体扰动的抗性。值得注意的是，我们发现 PTEN的蛋白磷酸酶活性是维持正常核型所必需的， 细胞对纺锤体药物的敏感性此外，我们的数据显示，一个关键的有丝分裂激酶，polo样 激酶1（Plk1）是潜在的PTEN靶点。这些发现导致我们假设PTEN是必需的， 确保有丝分裂期间染色体的忠实遗传，并且PTEN的蛋白磷酸酶功能是 对于抑制异常的有丝分裂激酶活性以维持正常的核型至关重要。为了验证这一 假设，我们提出两个具体目标如下。在目标1中，我们将展示有丝分裂染色体 不稳定性是PTEN缺陷普遍表型结果。我们将使用Pten条件敲除 白血病动物模型和Pten磷酸酶缺陷小鼠模型，以验证潜在的致病性 PTEN缺陷与核型改变的关系。在目标2中，我们将定义抑制性 Pk1和PTEN之间的信号联系，并阐明其平衡相互作用的机制 有助于核型保真度和肿瘤抑制。使用细胞和分子生物学方法，我们 将描述PTEN作为一种必需的有丝分裂磷酸酶的特征，并证明Plk1是PTEN的蛋白靶点。 维持有丝分裂染色体稳定性的PTEN磷酸酶。成功实现这些目标将 提供了深入了解的机制，从而PTEN缺陷触发有丝分裂缺陷和染色体 不稳定，从而导致肿瘤发生。该项目的新发现将为以下方面提供新的视角： 进一步的机制研究和治疗人类癌症的治疗策略的未来发展。