Determining how cell growth triggers cell division

该项目的首要目标是了解细胞生长如何触发酵母细胞分裂， 哺乳动物细胞解决这个问题有可能彻底改变我们对细胞分裂的理解 在自然发育环境和疾病中都受到调节。我们的工作对以下方面具有根本性的影响： 了解细胞形态的最基本方面，细胞大小，是如何控制的，并可以识别新的 可以合理地在癌症治疗中靶向的分子机制。 我的实验室最近在理解生长如何在萌芽中引发分裂方面有了突破性的发现 酵母虽然预期生长将增加细胞周期蛋白依赖性激酶的活性， (Cdk)但事实并非如此。相反，我们发现细胞生长的作用是相反的， 方式细胞生长通过稀释抑制细胞分裂的蛋白质Whi5来触发分裂。 这个MIRA项目旨在利用我们的突破性发现，了解增长如何引发分裂， 酵母，以了解酵母中的潜在转录机制，并了解这是如何工作的， 哺乳动物细胞由于哺乳动物基因组编辑技术的快速发展， 让我们能够在内源基因座标记细胞周期调节因子。我们现在可以第一次测量 几乎任何蛋白质在其内源基因座表达的浓度变化的动态 生长和分裂的细胞。为了确定生长与分裂之间的联系机制，我们将研究细胞如何 大小和生长影响单细胞分辨率下关键细胞周期调节剂的浓度。另外我们 目的是在酵母和不同的人类细胞类型中研究转录作为全基因组细胞大小的函数 以确定潜在的分子机制。

The overarching goal of this project is to understand how cell growth triggers cell division in yeast and in mammalian cells. Solving this question of has the potential to revolutionize our understanding of how cell division is regulated in both natural developmental contexts and in disease. Our work has fundamental implications for understanding how the most basic aspect of cell morphology, cell size, is controlled, and may identify novel molecular mechanisms that can rationally be targeted in cancer therapies. My laboratory recently made a breakthrough discovery in understanding how growth triggers division in budding yeast. While it was expected that growth would act to increase the activities of the cyclin-dependent kinases (Cdk) known to promote cell division, this is not the case. Rather, we found that cell growth acts in the opposite manner. Cell growth triggers division by diluting a protein that inhibits cell division, Whi5. This MIRA project aims to leverage our breakthrough discovery in understanding how growth triggers division in yeast to understand the underlying transcriptional mechanism in yeast and to understand how this works in mammalian cells. This is now possible thanks to the rapid advances in mammalian genome editing technologies that allow us to tag cell cycle regulators at their endogenous loci. We can now measure, for the first time, the dynamics of concentration changes of almost any protein expressed from its endogenous locus in individual growing and dividing cells. To determine the mechanisms linking growth to division, we will examine how cell size and growth impacts the concentration of key cell cycle regulators at single cell resolution. In addition, we aim to examine transcription as a function of cell size genomewide in both yeast and diverse human cell types to identify the underlying molecular mechanisms.