Role of PTEN in Chromosome Segregation and its Importance for Tumor Suppression

PTEN 在染色体分离中的作用及其对肿瘤抑制的重要性

• 批准号: 8862427
• 负责人: Jan M. van Deursen
• 金额: $ 32.99万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8862427
• 关键词: AKT inhibition; Affect; Alleles; Ally; Anaphase; Aneuploidy; Automobile Driving; Binding; Biochemical; Biological; Biological Models; Biological Process; Cancer Biology; Cancer Patient; Cell Death; Cell Proliferation; Cells; Chromosome Segregation; Chromosomes; Clinical; DLG1 gene; Data; Development; Ectopic Expression; Embryo; Ensure; Fibroblasts; Foundations; Frequencies; Genes; Goals; Human; Human Characteristics; Knowledge; Lesion; Lipids; Malignant Neoplasms; Mitosis; Mitotic; Mitotic Checkpoint; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutate; Mutation; Outcome; PTEN gene; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Preventive; Property; Prostatic Intraepithelial Neoplasias; Protein Binding Domain; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; RNA Interference; Role; Signal Transduction; Splenocyte; Testing; Therapeutic; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cancer cell; cell transformation; design; improved; innovation; insight; loss of function; mouse model; neoplastic; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; restoration; treatment strategy; tripolyphosphate; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The PTEN tumor suppressor gene is mutated, deleted or expressed at reduced levels in a large proportion of human cancers. PTEN is a lipid and protein phosphatase that negatively regulates phosphoinositol-3-kinase (PI3K)/AKT signaling by dephosphorylating phosphatidylinositol-3, 4, 5-triphosphate (PIP3). Unrestrained PI3K/AKT signaling leads to increased cell proliferation and reduced cell death, thereby driving tumorigenesis. Although antagonizing PI3K/AKT signaling is considered the primary physiological role of PTEN and its most relevant property as a tumor suppressor, PTEN may have additional tumor suppressive functions, for instance as a guardian of structural chromosome integrity. However, there is an incomplete understanding of the full repertoire of the normal and tumor suppressive PTEN functions and the extent to which PTEN mutations found in human cancer affect each of these functions. This represents a critical barrier that is slowing down progress toward improving treatment strategies for a large segment of cancer patients. We provide preliminary data that point to a novel biological function of PTEN in ensuring accurate chromosome segregation in mitosis and maintaining chromosome number stability. The central objective of this application is to decipher how mechanistically PTEN regulates proper chromosome segregation, and to determine the extent to which loss of this function contributes to malignant cell transformation, with the ultimate goal to exploit this knowledge for preventive and therapeutic purposes. Our central hypothesis is that PTEN, through its PDZ-interaction domain, regulates proper chromosome segregation in mitosis and that this novel function represents a critical tumor protective function of PTEN. We will test this hypothesis by pursuing two specific aims. In the first aim, we will determine the mechanism by which PTEN regulates proper chromosome segregation by using mouse embryonic fibroblasts (MEFs) from Pten+/- and other mutant mouse strains in combination with a comprehensive set of cell biological and biochemical approaches. In the second aim, we will establish the role of the Pten PDZ- interaction domain in normal development and tumor suppression using a newly generated "knockin" mouse strain that lacks this domain. We will determine the mitotic, developmental and cancer phenotypes of mice that are heterozygous and homozygous for this "knockin" allele and compare these to those of Pten+/- mice. The expected overall impact of this innovative proposal is that it will fundamentally advance our mechanistic understanding of the normal and neoplastic functions of the second most frequently mutated tumor suppressor gene in human cancer. This knowledge will lay the foundation for development of new therapeutic strategies that will improve the clinical outcome of cancer patients with alterations in PTEN, in addition to conceptually advancing the fields of mitosis and cancer biology.

描述(申请人提供)：PTEN肿瘤抑制基因在很大比例的人类癌症中发生突变、缺失或表达水平降低。PTEN是一种脂质和蛋白磷酸酶，通过使磷脂酰肌醇-3，4，5-三磷酸(PIP3)去磷酸化，负向调节PI3K/AKT信号转导。不受抑制的PI3K/AKT信号导致细胞增殖增加，细胞死亡减少，从而推动肿瘤的发生。尽管拮抗PI3K/AKT信号被认为是PTEN的主要生理作用及其作为肿瘤抑制因子的最相关性质，但PTEN可能还具有其他的肿瘤抑制功能，例如作为结构染色体完整性的守护者。然而，对于正常和肿瘤抑制PTEN功能的完整谱系，以及在人类癌症中发现的PTEN突变对这些功能的影响程度，目前还没有完全的了解。这是一个严重的障碍，正在减缓改善大部分癌症患者治疗策略的进展。我们提供的初步数据表明，PTEN在确保有丝分裂中准确的染色体分离和维持染色体数量稳定方面具有新的生物学功能。这项应用的中心目标是破译PTEN如何机械地调节适当的染色体分离，并确定这一功能的丧失在多大程度上有助于恶性细胞转化，最终目的是利用这一知识用于预防和治疗目的。我们的中心假设是，PTEN通过其PDZ相互作用结构域，调节有丝分裂中适当的染色体分离，这一新功能代表了PTEN的一个关键的肿瘤保护功能。我们将对此进行测试 通过追求两个具体目标来进行假设。在第一个目标中，我们将通过使用来自Pten+/-的小鼠胚胎成纤维细胞(MEF)和其他突变小鼠品系，结合一套全面的细胞生物学和生化方法来确定PTEN调节适当的染色体分离的机制。在第二个目标中，我们将利用新产生的缺乏Pten PDZ相互作用结构域的小鼠品系来确定该结构域在正常发育和肿瘤抑制中的作用。我们将确定这种“敲门”等位基因杂合和纯合的小鼠的有丝分裂、发育和癌症表型，并将这些表型与Pten+/-小鼠进行比较。这一创新建议的预期总体影响是，它将从根本上促进我们对人类癌症中第二频繁突变的肿瘤抑制基因的正常和肿瘤功能的机制理解。这些知识将为开发新的治疗策略奠定基础，这些策略将改善PTEN基因改变的癌症患者的临床结果，并在概念上推进有丝分裂和癌症生物学领域的发展。