SIGNALING PATHWAYS THAT REGULATE MITOSIS

描述（来自应用程序）：在细胞分裂期间复制染色体 平均分布到子细胞中--这个过程称为有丝分裂。的 在正常细胞中引起有丝分裂的生化事件是不明确的。 我们的长期目标是阐明调节 正常细胞中的纺锤体动力学和染色体分离。此外，我们在 有兴趣确定这些途径中的错误是否有助于 肿瘤发生 我们将集中在有丝分裂中一个特定的信号通路的作用， 丝裂原活化蛋白激酶（MAPK）级联反应。我们对MAP激酶的兴趣在于 我们发现它是正常有丝分裂进程所必需的， 并在有丝分裂过程中维持微管的动力学性质， 爪蟾卵提取物。这表明MAP激酶在调节 有丝分裂纺锤体MAP激酶与纺锤体两极相关， 在哺乳动物细胞M期期间的动粒和中间体进一步表明， 在有丝分裂中扮演着多重角色从机制上讲， MAPK信号传导如何参与介导M期进展。我们打算 利用爪蟾卵提取物系统来剖析MAP激酶激活是如何 在有丝分裂过程中被调节。此外，我们将使用生物化学和细胞 确定哺乳动物有丝分裂中MAP激酶功能的方法 细胞我们假设有丝分裂时MAPK信号对于调节细胞凋亡是至关重要的。 协调纺锤体动力学和染色体分离的过程 在细胞分裂期间。为了验证这一假设，我们提出了三个具体目标： 1.定义由MAPK信号调节的有丝分裂的细胞事件 在哺乳动物细胞中。 2.确定MAPK在调节细胞凋亡的形成和功能中的作用。 有丝分裂纺锤体 3.确定调节MAPK激活的生化步骤， 分裂。 总之，我们建议阐明MAPK的调节和功能， 正常细胞的有丝分裂。最终，我们希望确定 有丝分裂期间MAP激酶的调节可能导致基因组不稳定性 与肿瘤进展有关。

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.