Maintenance of Chromosome Stability by the Hippo Tumor Suppressor Pathway

Hippo 肿瘤抑制途径维持染色体稳定性

• 批准号: 9175493
• 负责人: NEIL J. GANEM
• 金额: $ 32.9万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175493
• 关键词: Abnormal Cell; Aneuploid Cells; Aneuploidy; Biochemical; Biological; Biosensor; Cell division; Cell physiology; Cells; Cellular biology; Chromosomal Instability; Chromosomal Stability; Chromosome Segregation; Chromosome abnormality; Chromosomes; Clinical; Cytokinesis; Data; Defect; Development; Evolution; Failure; Fluorescence Resonance Energy Transfer; G1 Phase; Generations; Genetic; Goals; Growth; Human; In Vitro; LATS1 gene; Maintenance; Malignant Neoplasms; Methods; Mitosis; Mitotic; Molecular; Mutation; Normal Cell; Pathway interactions; Phenotype; Phosphotransferases; Ploidies; Proteinase-Activated Receptors; Proteins; RNA interference screen; Relapse; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Stress; Structural Chromosomal Abnormality; Testing; Tetraploidy; Time; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; Work; base; cancer cell; cell growth; daughter cell; design; experience; genome-wide; insight; killings; live cell imaging; neoplastic cell; novel; novel therapeutics; outcome forecast; research study; tumor initiation

Chromosome instability (CIN), broadly defined as the persistent acquisition of both numerical and structural chromosome aberrations, is a hallmark of solid tumors that is known to facilitate tumor initiation, progression, and relapse. Consequently, CIN confers poor clinical prognosis. The development of CIN is a multistep process: cells must not only acquire the genetic and/or cell biological defects that induce abnormal chromosome segregation, but they must also overcome the stresses imposed by aneuploidy that act to restrain subsequent proliferation. Over the past decade, significant efforts have focused on identifying the underlying mechanisms that produce chromosome missegregation in cancer cells. However, there remains a paucity of data describing the mechanisms that respond to abnormalities in chromosome number and limit proliferation. Consequently, how cells adapt to overcome these growth barriers in order to become CIN remains a key unresolved question in cancer cell biology. We recently discovered that the Hippo tumor suppressor pathway is activated following cytokinesis failure and that this limits the proliferation of the resulting tetraploid cells. In addition, our preliminary data suggest that inactivation of Hippo signaling is sufficient to promote CIN in non-transformed cells. Together, these findings suggest that the Hippo pathway may have a broadly relevant role in restraining the growth of cells harboring numerical chromosome abnormalities. The goal of this proposal is to elucidate the mechanistic role of the Hippo pathway in both sensing and responding to abnormal cell division and aneuploidy. The aims are: 1) To mechanistically define the role of the Hippo pathway in maintaining chromosome stability; 2) To determine the role of Hippo signaling in setting the mitotic clock; and 3) To identify cancer-relevant genetic regulators of Hippo pathway signaling.

染色体不稳定性（CIN），广义上定义为持续获得的数字和结构 染色体畸变是实体瘤的标志，已知其促进肿瘤的发生、发展和转移。 复发因此，CIN赋予不良的临床预后。CIN的发展是一个多步骤的过程：细胞 不仅必须获得诱导异常染色体分离的遗传和/或细胞生物学缺陷， 但是它们还必须克服由非整倍性施加的应力，所述应力用于抑制随后的增殖。 在过去十年中，大量的努力集中在确定产生 癌细胞中的染色体错误分离。然而，仍然缺乏数据来描述 对染色体数目异常作出反应并限制增殖的机制。因此如何 细胞适应克服这些生长障碍，以成为CIN仍然是一个关键的悬而未决的问题， 癌细胞生物学我们最近发现，Hippo肿瘤抑制通路在以下情况下被激活： 胞质分裂失败，并且这限制了所得四倍体细胞的增殖。另外我们 初步数据表明，Hippo信号转导的失活足以促进非转化细胞中的CIN。 细胞总之，这些研究结果表明，海马通路可能在抑制肿瘤细胞增殖方面具有广泛的相关作用。 染色体数目异常的细胞的生长。本提案的目的是阐明 Hippo通路在感知和响应异常细胞分裂中的机制作用， 非整倍性目的是：1）从机制上确定Hippo通路在维持染色体中的作用 稳定性; 2）确定Hippo信号传导在设置有丝分裂钟中的作用;和3）鉴定癌症相关的 Hippo信号通路的遗传调节因子。