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: 8238727
• 负责人: WEN H. SHEN
• 金额: $ 31.46万
• 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/8238727
• 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. PUBLIC HEALTH RELEVANCE: PTEN phosphatase is a potent tumor suppressor that is known to antagonize oncogenic pathways. This project will characterize a new function of PTEN in controlling cell division and identify Plk1 as a nuclear target of PTEN phosphatase that maintains mitotic fidelity and karyotypic stability. New findings from this study will elucidate how the novel PTEN-Plk1 signaling pathway prevents genomic instability and tumorigenesis, providing significant implications for development of new anti-cancer strategies.

描述（由申请人提供）：PTEN是人类癌症中最常突变的基因之一，并且由于其在保护染色体完整性中的重要作用，PTEN蛋白被认为是“基因组的监护人”。在缺乏功能性PTEN的细胞和组织中观察到的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错误分离和突出的多倍性，这表明PTEN在有丝分裂过程中起着控制基因组和核型稳定性的作用。异常有丝分裂过程中获得的染色体不稳定性在肿瘤的发生和发展中起着重要的作用。该研究项目的长期目标是建立新的概念，即PTEN在控制有丝分裂染色体稳定性中起重要作用，并且其维持有丝分裂保真度的功能是肿瘤抑制的主要驱动力。为了支持这一目标，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体化，并赋予细胞耐纺锤体扰动。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和细胞对纺锤体药物敏感性所必需的。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（Plk 1），是一个潜在的PTEN靶点。这些研究结果导致我们的假设，PTEN是必要的，以确保忠实的染色体遗传在有丝分裂和蛋白磷酸酶的功能，PTEN是至关重要的抑制异常有丝分裂激酶活性，以保持正常的核型。为了验证这一假设，我们提出了以下两个具体目标。在目标1中，我们将证明有丝分裂染色体不稳定性是一个普遍的表型结果的PTEN缺陷。我们将使用Pten条件性敲除白血病动物模型和一组Cowden综合征衍生的人淋巴母细胞样细胞系来验证PTEN缺陷和核型改变之间的潜在因果关系。在目标2中，我们将定义PTEN和Plk 1之间的抑制性信号联系，并阐明其平衡的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的方法，我们将表征为一个必不可少的有丝分裂磷酸酶的PTEN，并证明Plk 1是一个蛋白质靶点的PTEN磷酸酶，维持有丝分裂染色体的稳定性。这些目标的成功完成将提供深入了解PTEN缺陷触发有丝分裂缺陷和染色体不稳定性，从而导致肿瘤发生的机制。该项目的新发现将为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提供新的视角。 公共卫生相关性：PTEN磷酸酶是一种有效的肿瘤抑制剂，已知可拮抗致癌途径。该项目将描述PTEN在控制细胞分裂中的新功能，并将Plk 1鉴定为维持有丝分裂保真度和核型稳定性的PTEN磷酸酶的核靶点。这项研究的新发现将阐明新的PTEN-Plk 1信号通路如何防止基因组不稳定性和肿瘤发生，为开发新的抗癌策略提供重要意义。