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: 8340701
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8340701
• 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. PUBLIC HEALTH RELEVANCE: PTEN is the second most commonly mutated tumor suppressor in human cancer but the full repertoire of its normal and tumor suppressive functions is unclear, which is slowing down progress toward improving treatment strategies for a large segment of cancer patients. We have discovered a novel function of PTEN in accurate chromosome segregation. We propose to investigate how PTEN performs this function and how important it is for suppression of tumor formation. The studies are highly significant because the insights gained will lay the foundation for development of new therapeutic interventions that will improve the clinical outcome of cancer patients with mutations in PTEN.

描述（由申请人提供）：PTEN肿瘤抑制基因被突变，删除或以降低的水平表达，以很大一部分的人类癌症。 PTEN是一种脂质和蛋白质磷酸酶，通过去磷酸化磷酸化磷脂酰肌醇-3，4，5-三磷酸盐（PIP3），对磷酸肌醇-3-激酶（PI3K）/Akt信号进行负调节（PIP3）。不受约束的PI3K/AKT信号传导导致细胞增殖增加并减少细胞死亡，从而驱动肿瘤发生。尽管拮抗PI3K/AKT信号传导被认为是PTEN及其作为肿瘤抑制剂最相关特性的主要生理作用，但PTEN可能具有额外的肿瘤抑制功能，例如作为结构染色体完整性的监护人。但是，对正常和肿瘤抑制性PTEN功能的全部曲目有不完全的理解，以及人类癌症中PTEN突变影响的每一种功能的程度。这代表了一个关键的障碍，该障碍正在放缓改善大部分癌症患者治疗策略的进展。我们提供了初步数据，该数据指出了PTEN在确保有丝分裂中准确的染色体分离和维持染色体数稳定性方面的新生物学功能。该应用的核心目的是破译机械学上如何调节适当的染色体分离，并确定该功能损失导致恶性细胞转化的程度，其最终目标是利用这种知识来预防和治疗目的。我们的中心假设是，PTEN通过其PDZ交流结构域调节有丝分裂中的适当染色体分离，并且这种新功能代表了PTEN的关键肿瘤保护功能。我们将测试这个 通过追求两个具体目标来假设。在第一个目标中，我们将通过使用PTEN +/-和其他突变小鼠菌株的小鼠胚胎成纤维细胞（MEF）来确定PTEN调节适当的染色体分离的机制，并结合一组全面的细胞生物学和生物化学方法。在第二个目标中，我们将使用缺乏该结构域的新产生的“敲蛋白”小鼠菌株来确定PTEN PDZ相互作用结构域在正常发育和肿瘤抑制中的作用。我们将确定小鼠的有丝分裂，发育和癌症表型，这些小鼠对这个“敲击”等位基因是杂合且纯合的，并将其与PTEN +/-小鼠的等位基因进行了比较。这项创新提案的预期总体影响是，它将从根本上促进我们对人类癌症中第二种最常见的肿瘤抑制基因的正常和肿瘤功能的机械理解。这些知识将奠定新的治疗策略的发展基础，这些策略将改善PTEN改变的癌症患者的临床结果，除了概念上推进有丝分裂和癌症生物学领域。 公共卫生相关性：PTEN是人类癌症中第二常见突变的肿瘤抑制剂，但尚不清楚其正常和肿瘤抑制功能的全部曲目，这正在放缓改善大部分癌症患者治疗策略的进展。我们发现了PTEN在准确的染色体分离中的新功能。我们建议研究PTEN如何执行此功能以及它对抑制肿瘤形成的重要性。这些研究非常重要，因为获得的见解将为开发新的治疗干预措施的发展奠定基础，从而改善PTEN突变的癌症患者的临床结果。