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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 真核细胞在大小和形态上表现出非凡的多样性。由于每种细胞类型都具有独特的大小和形状，因此细胞生长的控制与细胞的形态、功能和特性是不可分割的。细胞的生长很可能是由非常复杂的机制控制的，因为单细胞生物可以在差异很大的生长条件下保持相同的大小和形状，而多细胞生物是由大小和形状差异很大的细胞组成的。在萌芽酵母和分裂酵母中的遗传实验都证明了细胞周期蛋白依赖性蛋白激酶在控制细胞生长中起着关键作用；然而，它们实现这一功能的分子机制却知之甚少。 我们的研究重点是了解在芽期酵母有丝分裂过程中，细胞周期蛋白依赖性蛋白激酶是如何协调细胞生长和细胞分裂的。有丝分裂周期蛋白依赖的激酶复合体失活导致细胞在G2/M期停滞期间持续生长，导致高度延长的细胞的形成。细长的细胞生长明显大于野生型细胞，这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期有一个复杂的信号网络控制细胞的生长。生化和遗传学数据表明，这个信号网络受有丝分裂CDK活性的调节，并在调节发芽酵母Wee1激酶的同源物中发挥重要作用，Wee1激酶已被证明在协调分裂酵母的细胞生长和有丝分裂中发挥着核心作用。我们最新的工作表明，Swe1直接与有丝分裂的CDK复合体和参与细胞生长的蛋白质结合，为协调细胞生长和细胞周期的长期神秘的分子机制提供了第一条线索。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机制。 我们工作的另一个主要焦点是了解控制细胞周期G1期的机制。G1期是细胞评估外部条件和细胞大小，然后决定是否进行新一轮细胞分裂的关键时期。G1期的细胞只有在达到临界大小并接收到适当的生长因子或营养物质形式的外部信号时，才会启动新一轮的细胞分裂。尽管已经确定了一些G1事件的关键调控因子，但我们仍然不了解整合细胞大小和外部信号与进入细胞周期的分子机制。我们已经发现了一种高度保守的蛋白质，这是进入发芽酵母进入G1期所必需的。此外，在上述有丝分裂信号网络中发挥作用的一些蛋白质似乎也参与了通过G1的控制。我们目前正在用我们用来描述有丝分裂信号网络的相同的生化和遗传方法来表征G1调控。