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

描述（由申请人提供）：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，通过去磷酸化磷脂酰肌醇- 3,4,5 -三磷酸（PIP3）负调控磷酸肌醇-3激酶(PI3K)/AKT信号通路。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特性，但PTEN可能具有其他肿瘤抑制功能，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的全部功能，以及在人类癌症中发现的PTEN突变对这些功能的影响程度，人们的理解并不完整。这代表了一个关键的障碍，它正在减缓改善大部分癌症患者的治疗策略的进展。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。本应用程序的中心目标是破译PTEN如何机制地调节适当的染色体分离，并确定该功能的丧失对恶性细胞转化的影响程度，最终目标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，这种新功能代表了PTEN的关键肿瘤保护功能。我们将对此进行测试

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.