CHROMOSOME MOVEMENT IN PROMETAPHASE

前期染色体运动

• 批准号: 2857195
• 负责人: GARY J. GORBSKY
• 金额: $ 19.26万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2857195
• 关键词: DNA topoisomerases; biological signal transduction; cell cycle; centromere; chromosome movement; electrospray ionization mass spectrometry; enzyme activity; gas chromatography mass spectrometry; gel electrophoresis; gene expression; image processing; immunofluorescence technique; immunoprecipitation; laboratory mouse; laboratory rabbit; microinjections; mitotic spindle apparatus; monoclonal antibody; phosphoprotein phosphatase; phosphorylation; polymerase chain reaction; protein kinase; protein structure; western blottings

In the presence of misaligned chromosomes, normal somatic cells arrest in M phase. This surveillance system or cell cycle checkpoint prevents the generation of progeny cells with too many or too few chromosomes. The long-term objective of this work proposed here application is delineating all steps of the signaling pathways that regulate mitotic cell cycle checkpoints. The working hypothesis is that signals blocking the onset of anaphase emanate from "relaxed" kinetochores, those lacking stable microtubule attachments. Mechanical tension imparted by the attachment of mitotic spindle microtubules leads to conformational changes of in kinetochore components and turns off the checkpoint signal. The checkpoint signal at the kinetochore involves protein phosphorylation recognized by the 3F3/2 monoclonal antibody. The specific aims of this proposal are: dissecting the molecular nature of the 3F3/2 phosphoepitope, and determining how it participates in checkpoint regulation, identifying the kinase that creates the 3F3/2 phosphoepitope and determining how it is regulated during the cell cycle, and lastly determining how kinase activity is regulated by tension. M phase checkpoints play an essential role in assuring equal segregation of chromosomes in mitosis and meiosis. In cancer, cell cycle checkpoints are often faulty. In some instances this may, in fact, potentiate the induction of apoptosis by tumor therapies. However, chromosome imbalances also contribute to the progression of malignancy in tumors. In germ cell maturation, chromosomal imbalances induced during meiosis are a significant cause of birth defects. Understanding how the M phase checkpoints are regulated promises new ways of understanding and novel avenues for intervention in human cancer and birth defects.

在染色体排列不齐的情况下，正常的体细胞 年被捕 M阶段。 这个监视系统或细胞周期检查点 防止 染色体过多或过少的后代细胞。 的 本文提出的长期工作目标是 划定 调节有丝分裂细胞的所有信号通路 周期 检查站 目前的假设是， 发作 的后期来自于“放松的”动粒，那些缺乏 稳定 微管附着 机械张力由 附接 有丝分裂纺锤体微管的构象变化， 在 动粒组件并关闭检查点信号。 的 在动粒的检查点信号涉及蛋白质 磷酸化 被3F 3/2单克隆抗体识别。 的具体目标 这 建议是：解剖3F 3/2的分子性质 磷酸表位，并确定它如何参与检查点 调节，确定产生3F 3/2的激酶 磷酸表位 并确定它在细胞周期中是如何调节的， 最后 确定激酶活性如何受张力调节。 M期 检查站在确保平等隔离 有丝分裂和减数分裂中的染色体。 在癌症中，细胞周期 检查站 往往是错误的。 事实上，在某些情况下， 的 通过肿瘤治疗诱导细胞凋亡。 然而，染色体 不平衡也有助于恶性肿瘤的进展， 肿瘤的 在生殖细胞成熟过程中， 减数分裂 是导致出生缺陷的重要原因。 了解M 相 检查站的管制承诺新的理解方式， 小说 干预人类癌症和出生缺陷的途径。