Determining how cell growth triggers cell division

这个项目的首要目标是了解细胞生长是如何在酵母中和在 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方式的理解 在自然发育环境和疾病中都受到调控。我们的工作对 了解细胞形态的最基本方面，即细胞大小是如何被控制的，并可能识别出新的 可以合理地作为癌症治疗靶点的分子机制。 我的实验室最近在理解生长如何触发萌芽中的分裂方面有了突破性的发现 酵母。虽然人们预计生长会增加细胞周期蛋白依赖性蛋白激酶的活性 (CDK)已知能促进细胞分裂，但事实并非如此。相反，我们发现细胞的生长与之相反 举止。细胞生长通过稀释一种抑制细胞分裂的蛋白质来触发分裂，WHI5。 此Mira项目旨在利用我们的突破性发现，了解增长如何在 了解酵母中潜在的转录机制，并了解这一机制在 哺乳动物细胞。多亏了哺乳动物基因组编辑技术的快速进步，这现在成为可能 这使我们能够标记细胞周期调节器在其内源位置。我们现在可以第一次测量 几乎所有从其内源位点表达的蛋白质在个体中的浓度变化动态 生长和分裂细胞。为了确定将生长和分裂联系起来的机制，我们将研究细胞如何 在单个细胞分辨率下，大小和生长影响关键细胞周期调节因子的浓度。此外，我们 目的研究酵母和不同人类细胞类型中转录水平与细胞大小的关系 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.