Control of Cell Growth and Size

细胞生长和大小的控制

• 批准号: 10417215
• 负责人: Douglas R. Kellogg
• 金额: $ 53.69万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-28 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417215
• 关键词: Back; Cell Cycle; Cell Cycle Progression; Cell Size; Cell membrane; Cells; Defect; Ensure; Eukaryotic Cell; Future; Goals; Growth; Knowledge; Life; Malignant Neoplasms; Maps; Measures; Membrane; Normal Cell; Nutrient; Pathology; Phosphatidylserines; Proliferating; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Translating; Vesicle; Work; Yeasts; cancer cell; cell growth; improved; novel; recruit

The goal of our work is to discover fundamental mechanisms that control cell growth and size in all eukaryotic cells. Our recent work has focused on two key questions: 1. How do cells measure and limit growth to control cell size? In all cells, key cell cycle transitions occur only when sufficient growth has occurred, which ensures that proliferating cells maintain a specific size. Thus, cells must convert growth to a proportional signal that triggers cell cycle progression when it reaches a threshold. The mechanisms by which cells measure growth and trigger cell cycle transitions have remained deeply mysterious. Our recent work suggests that vesicles that drive plasma membrane growth deliver phosphatidylserine to the growing membrane, which recruits conserved signaling proteins to generate a signal that is proportional to the extent of growth. Furthermore, we discovered a signaling pathway that could read the growth-dependent signal and trigger cell cycle progression when it reaches a threshold. Growth-dependent signaling suggests a simple and broadly applicable solution to control of cell growth and size. 2. What are the signals that control cell growth and size? Observations reaching back over 60 years point to close relationships between control of cell growth and size. Thus, growth rate is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. These relationships appear to hold across all orders of life, which suggest that they reflect fundamental principles, yet the underlying mechanisms have remained elusive. We discovered that signals arising from a conserved TORC2 signaling network enforce proportional relationships between nutrient availability, cell growth, and cell size. For example, our work suggests that TORC2-dependent signals that set growth rate also set the threshold amount of growth required for cell cycle progression, which would provide a simple mechanistic explanation for the proportional relationship between cell size and growth rate. Together, these new discoveries support transformational hypotheses that could broadly explain how cell growth and size are controlled. In our future work, we will test the key hypotheses arising from our discoveries, while also carrying out mechanistic analysis to further map the remarkable signaling networks that control cell growth and size. We will also begin translating our discoveries in yeast into an understanding of how cell growth and size are controlled in vertebrate cells.

我们工作的目的是发现控制细胞生长和大小的基本机制 真核细胞。我们最近的工作重点是两个关键问题： 1。细胞如何测量和限制生长以控制细胞大小？在所有细胞中，关键的细胞周期过渡 仅当发生足够的生长时就会发生，这可以确保增殖细胞保持特定 尺寸。因此，细胞必须将生长转换为比例信号，该信号会触发细胞周期的进展 达到阈值。细胞测量生长和触发细胞周期过渡的机制 仍然非常神秘。我们最近的工作表明驱动质膜的囊泡 生长将磷脂酰丝氨酸传递到生长的膜，该膜募集了保守的信号蛋白 产生与生长程度成正比的信号。此外，我们发现了一个信号 可以读取生长依赖性信号和触发细胞周期进程的途径 阈值。与生长有关的信号传导提出了一种简单且广泛的解决方案，以控制 细胞生长和大小。 2。控制细胞生长和大小的信号是什么？观察到60多年来 指向控制细胞生长和大小之间的密切关系。因此，增长率与 养分可用性，细胞大小与生长速率成正比，生长速率与细胞大小成正比。 这些关系似乎在所有的生活顺序中都存在，这表明它们反映了基本 原则，但基本机制仍然难以捉摸。我们发现引起的信号 从保守的TORC2信号网络实现营养之间的比例关系 可用性，细胞生长和细胞大小。例如，我们的工作表明TORC2依赖性信号 该设定的增长率还设置了细胞周期进程所需的生长阈值，这 将为细胞大小和细胞大小之间的比例关系提供一个简单的机械解释 增长率。 这些新发现共同支持了转化假设，这些假设可以广泛解释细胞的方式 生长和大小受到控制。在未来的工作中，我们将测试由我们的关键假设 发现，同时还进行机械分析以进一步映射出色的信号网络 控制细胞的生长和大小。我们还将开始将酵母中的发现转化为 了解在脊椎动物细胞中如何控制细胞生长和大小。