SIGNALING PATHWAYS THAT REGULATE MITOSIS

调节有丝分裂的信号通路

• 批准号: 6254791
• 负责人: THOMAS M GUADAGNO
• 金额: $ 23.69万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6254791
• 关键词: Xenopus; biochemistry; biological signal transduction; cell biology; cell component structure /function; cell cycle; cell free system; cell growth regulation; cell line; cell proliferation; chromosome aberrations; chromosome movement; developmental genetics; enzyme induction /repression; enzyme inhibitors; enzyme mechanism; flow cytometry; fluorescence microscopy; guanine nucleotide binding protein; mitogen activated protein kinase; mitotic spindle apparatus; protein localization; protein protein interaction; video microscopy

DESCRIPTION (from the application): During cell division duplicated chromosomes are distributed equally into daughter cells- a process termed mitosis. The biochemical events that bring about mitosis in normal cells are ill defined. Our long-term objectives are to elucidate the signaling pathways that regulate spindle dynamics and chromsome segregation in normal cells. In addition, we are interested in determining whether errors in these pathways contribute to tumorigenesis. We will focus on the role of a particular signaling pathway at mitosis, the mitogen-activated protein kinase (MAPK) cascade. Our interest in MAP kinase was stimualted by our discovery that it is required for normal mitotic progression and for maintaining the dynamic properties of microtubules during mitosis in Xenopus egg extracts. This indicates a role for MAP kinase in the regulation of the mitotic spindle. The fact that MAP kinase associates with spindle poles, kinetichores and midbody during M phase in mammalian cells further suggests it plays multiple roles throughout mitosis. Mechanistically, little is known about how MAPK signaling is involved in mediating M-phase progression. We intend to exploit the Xenopus egg extract system to dissect how MAP kinase activation is regulated during mitosis. Furthermore, we will use biochemical and cellular approaches to determine the function of MAP kinase at mitosis in mammalian cells. We hypothesize that MAPK signaling at mitosis is critical for regulating the processes that coordinate spindle dynamics and chromosome segregation during cell division. To test this hypothesis, we propose three specific aims: 1. Define the cellular events of mitosis that are regulated by MAPK signaling in mammalian cells. 2. Determine the role MAPK plays in regulating the formation and function of the mitotic spindle apparatus. 3. Determine the biochemical steps that regulate MAPK activation during mitosis. In summary, we propose to elucidate the regulation and function of MAPK at mitosis in normal cells. Ultimately, we hope to establish whether defects in MAP kinase regulation during mitosis may contribute to genomic instabilities associated with tumor progression.

描述(来自申请)：在细胞分裂过程中复制染色体 平均分布到子细胞中--这一过程称为有丝分裂。这个 导致正常细胞有丝分裂的生化事件定义不清。 我们的长期目标是阐明调节 正常细胞的纺锤体动力学和染色体分离。此外，我们正在 有兴趣确定这些通路中的错误是否会导致 肿瘤发生学。 我们将专注于有丝分裂中一条特殊的信号通路的作用，即 丝裂原活化蛋白激酶(MAPK)级联反应。我们对MAP激酶的兴趣是 我们发现它是正常有丝分裂进程所必需的，这一发现令人沮丧 并在有丝分裂过程中维持微管的动态特性 非洲爪哇卵萃取物。这表明MAP激酶在细胞周期调控中发挥作用。 有丝分裂的纺锤体。事实上，MAPK与纺锤体极相关联， 哺乳动物细胞中M期的运动中心和中间体进一步表明 在整个有丝分裂过程中扮演多种角色。从机制上讲，人们对此知之甚少 MAPK信号是如何参与调节M期进展的。我们打算 利用非洲爪哇卵子提取系统剖析MAP激酶激活是如何 在有丝分裂过程中受到调节。此外，我们将使用生化和细胞 确定MAP激酶在哺乳动物有丝分裂中功能的方法 细胞。我们假设MAPK信号在有丝分裂中对调节至关重要。 协调纺锤体动力学和染色体分离的过程 在细胞分裂过程中。为了验证这一假设，我们提出了三个具体目标： 1.确定有丝分裂中受MAPK信号调控的细胞事件 在哺乳动物细胞中。 2.确定MAPK在调节MAPK的形成和功能中的作用 有丝分裂的纺锤体。 3.确定调节MAPK激活的生化步骤 有丝分裂。 综上所述，我们建议在以下地址阐明MAPK的调控和功能 正常细胞中的有丝分裂。最终，我们希望确定是否存在缺陷 有丝分裂过程中MAP激酶的调节可能导致基因组不稳定 与肿瘤进展有关。