Regulation of Mitosis by Proteolysis in Yeast

酵母中蛋白水解作用对有丝分裂的调节

• 批准号: 7898017
• 负责人: ANGELIKA B AMON
• 金额: $ 21.39万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-31 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898017
• 关键词: Accounting; Address; Affect; Alleles; Anabolism; Anaphase; Aneuploidy; Biochemical; Biological; Biological Assay; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Proliferation; Cells; Chromosomes; Ensure; Exhibits; GTPase-Activating Proteins; Genes; Genetic; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Human; In Vitro; Infertility; Light; Malignant Neoplasms; Mediating; Mitosis; Mitotic; Mitotic Activity; Molecular; Mothers; Pathway interactions; Phase Transition; Phosphotransferases; Plasmids; Positioning Attribute; Protein Kinase; Proteolysis; Reading; Regulation; Reporter; Saccharomyces cerevisiae; Signal Transduction; Spontaneous abortion; Techniques; Testing; Yeasts; base; cell cortex; chromosome loss; daughter cell; in vivo; loss of function; mutant; prevent; protein complex; segregation; spindle pole body; tumor

DESCRIPTION (provided by applicant): Aneuploidy is a hallmark of cancer and the leading cause of miscarriages in humans. Determining the causes and consequences of aneuploidy is thus vital for understanding the principles underlying tumor formation and infertility. The long-term goal of our studies is to define the mechanisms that prevent chromosome mis-segregation and thus aneuploidy and the consequences of aneuploidy on cell proliferation at the molecular level. The three Specific Aims of this proposal are aimed at addressing these two questions. In Specific Aim 1, we use molecular and biochemical approaches to determine how the Mitotic Exit Network, a regulatory network essential for promoting exit from mitosis, is regulated. In particular, we will determine, how the GTPase of this pathway is controlled and, using this information, develop in vivo read outs for the activity of the GTPase. In Specific Aim 2 we will investigate how a surveillance mechanism known as the spindle position checkpoint affects MEN activity. Specifically, we will determine how the spindle position checkpoint component Kin4 regulates the MEN and test the hypothesis that division of the yeast cell in a MEN inhibitory zone (the mother cell) and a MEN activating zone (the bud) is the mechanism whereby spindle position is sensed in yeast. In Specific Aim 3 will characterize the consequences of aneuploidy. We have discovered that many yeast strains with one or two extra chromosomes are delayed in G1. We will determine the cause(s) of this G1 delay. Furthermore we will identify genes that mediate this G1 delay by identifying loss of function alleles and high copy plasmids that shorten the G1 delay in aneuploids. Their analysis will shed light on how aneuploidy delays cell cycle progression.

描述（由申请人提供）：非整倍性是癌症的标志，也是人类流产的主要原因。因此，确定非整倍性的原因和后果对于理解肿瘤形成和不育的原理至关重要。我们研究的长期目标是定义防止染色体错误分离的机制，从而定义非整倍性以及非整倍性在分子水平上细胞增殖的后果。该提案的三个具体目的旨在解决这两个问题。在特定的目标1中，我们使用分子和生化方法来确定有丝分裂出口网络是如何调节有丝分裂网络的，这是促进有丝分裂出口必不可少的调节网络。特别是，我们将确定该途径的GTPase如何受到控制，并使用此信息为GTPase的活性开发体内读数。在特定目标2中，我们将研究称为纺锤位置检查点的监视机制如何影响男性活动。具体而言，我们将确定主轴位置检查点组件KIN4如何调节男性并测试男性抑制区（母细胞）和男性激活区（芽）中酵母细胞的划分的假设，是在酵母中感测纺锤位置的机制。在特定目标中，3将表征非整倍性的后果。我们发现，G1中有许多具有一两个额外染色体的酵母菌菌株被延迟。我们将确定此G1延迟的原因。此外，我们将通过识别函数等位基因的丧失和高拷贝质粒的损失来识别介导该G1延迟的基因，从而缩短了非倍倍体的G1延迟。他们的分析将阐明非整倍性如何延迟细胞周期的进程。