MOLECULAR MECHANISMS REQUIRED FOR COORDINATION OF CELL GROWTH AND CELL DIVISION

协调细胞生长和细胞分裂所需的分子机制

• 批准号: 7602187
• 负责人: Douglas R. Kellogg
• 金额: $ 0.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602187
• 关键词: Biochemical Genetics; Cell Cycle; Cell Size; Cell division; Cells; Commit; Complex; Computer Retrieval of Information on Scientific Projects Database; Condition; Cyclin-Dependent Kinases; Data; Eukaryotic Cell; Event; Failure; Fission Yeast; Funding; Future; G1 Phase; G2/M Arrest; Genetic; Grant; Growth; Growth Factor; Homologous Gene; Institution; Mitosis; Mitotic; Molecular; Morphology; Numbers; Nutrient; Organism; Phosphotransferases; Play; Proteins; Research; Research Personnel; Resources; Role; Saccharomycetales; Shapes; Signal Transduction; Source; United States National Institutes of Health; Work; Yeasts; cell growth; cell type; numb protein; protein function; research study; size

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Eukaryotic cells show extraordinary diversity in size and morphology. Since each cell type is characterized by a unique size and shape, the control of cell growth is integral to cellular form, function, and identity. It is likely that cell growth is controlled by highly intricate mechanisms, since single-celled organisms can maintain the same size and shape over widely varying growth conditions, and multicellular organisms are composed of cells of widely differing size and shape. Genetic experiments in both budding yeast and fission yeast have demonstrated that cyclin-dependent kinases play a critical role in controlling cell growth; however, the molecular mechanisms by which they do so are poorly understood. The focus of our research is to understand how cyclin-dependent kinases coordinate cell growth and cell division during mitosis in budding yeast. Inactivation of mitotic cyclin-dependent kinase complexes results in continuous cell growth during a G2/M arrest, causing the formation of highly elongated cells. The elongated cells grow significantly larger than wild type cells, indicating a severe failure in the mechanisms that control cell size and cell growth. We have found that an intricate signaling network functions during G2/M to control cell growth. Biochemical and genetic data argue that this signaling network is regulated by mitotic CDK activity and plays an important role in regulating the budding yeast homolog of the Wee1 kinase, which has been shown to play a central role in coordinating cell growth and mitosis in fission yeast. Our most recent work suggests that Swe1 associates directly with mitotic Cdk complexes and proteins involved in cell growth, providing the first clues to the long mysterious molecular mechanisms that coordinate cell growth with the cell cycle. A focus of our future work will be to use biochemical and genetic approaches to understand the molecular signaling mechanisms that coordinate cell growth and cell division. Another major focus of our work is to understand the mechanisms that control passage through the G1 phase of the cell cycle. G1 is a crucial period where cells assess external conditions and cell size, and then make a decision regarding whether to commit to a new round of cell division. Cells in G1 initiate a new round of cell division only when they have reached a critical size and have received the appropriate external signals in the form of growth factors or nutrients. Although a number of key regulators of G1 events have been identified, we still do not understand the molecular mechanisms that integrate cell size and external signals with entry into the cell cycle. We have discovered a highly conserved protein that is required for entry into G1 in budding yeast. In addition, a number of the proteins that function in the mitotic signaling network described above also appear to be involved in controlling passage through G1. We are currently characterizing G1 control using the same biochemical and genetic approaches that we are using to characterize mitotic signaling networks.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 真核细胞在大小和形态上表现出非凡的多样性。由于每种细胞类型的特征都具有唯一的大小和形状，因此细胞生长的控制是细胞形式，功能和身份的组成部分。细胞生长可能受到高度复杂的机制的控制，因为单细胞生物可以维持相同的大小和形状在广泛不同的生长条件下，并且多细胞生物由大小和形状差异的细胞组成。在萌芽酵母和裂变酵母中的基因实验表明，依赖细胞周期蛋白的激酶在控制细胞生长中起着关键作用。但是，他们这样做的分子机制知之甚少。 我们研究的重点是了解细胞周期蛋白依赖性激酶如何在发芽酵母有丝分裂期间如何求解细胞的生长和细胞分裂。有丝分裂细胞周期蛋白依赖性激酶复合物的失活导致G2/m停滞期间的连续细胞生长，导致形成高度伸长的细胞。细长的细胞生长明显大于野生型细胞，表明控制细胞大小和细胞生长的机制严重失败。我们发现，在G2/M期间，复杂的信号网络功能以控制细胞生长。生化和遗传数据认为，该信号网络受丝分裂CDK活性的调节，并且在调节WEE1激酶的发芽酵母同源物中起着重要作用，该酶的发芽酵母同源物已被证明在协调裂变酵母中的细胞生长和有丝分裂方面起着核心作用。我们最近的工作表明，SWE1与涉及细胞生长的有丝分裂CDK复合物和蛋白质相关联，为长期神秘的分子机制提供了第一个线索，这些线索与细胞周期相结合。 我们未来工作的重点将是使用生化和遗传方法来了解协调细胞生长和细胞分裂的分子信号传导机制。 我们工作的另一个主要重点是了解控制通过细胞周期G1阶段的机制。 G1是一个至关重要的时期，细胞评估外部条件和细胞大小，然后就是否要进行新的细胞分裂做出决定。 G1中的细胞只有在达到临界大小并以生长因子或营养形式的适当外部信号时才会启动新的细胞分裂。尽管已经确定了许多G1事件的关键调节剂，但我们仍然不了解将细胞大小和外部信号与进入细胞周期的进入的分子机制。我们发现了一种高度保守的蛋白质，该蛋白需要进入萌芽酵母中的G1。此外，上述有丝分裂信号网络中功能的许多蛋白质似乎也参与控制通过G1的传段。我们目前正在使用与我们用来表征有丝分裂信号网络相同的生化和遗传方法来表征G1控制。