Cell-cycle-dependent cell polarity control

细胞周期依赖性细胞极性控制

• 批准号: 10770300
• 负责人: Maitreyi Das
• 金额: $ 31.3万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10770300
• 关键词: Cell; cycle; dependent; cell; polarity

PROJECT SUMMARY/ABSTRACT Polarized cells in retain their shape in every cell cycle and this is essential to their proper function. Anomalies in polarized cell shape can result in cancer, metabolic disorders, and loss of tissue integrity. Here, we will investigate a long-standing question of how cells consistently regain their polarity after each round of division. This investigation will be conducted using the fission yeast, Schizosaccharomyces pombe model system that provides many well characterized genetic tools to manipulate conserved proteins that influence cell shape following division. Cdc42 is the major regulator of polarized growth. In fission yeast, cells halt polarized Cdc42 activation and consequent growth at the cell ends during mitosis. After completion of division, these cell ends resume Cdc42 activation and cell growth. After division, Cdc42 activation and polarized growth always resumes in a monopolar manner from the old end that pre-exists from the previous generation. The cell transitions to bipolar growth when Cdc42 activation also resumes at the newly formed cell end in the G2 phase of the cell cycle. Our preliminary data indicate that resumption of Cdc42 activation at the old end after division and transition to bipolar activation in G2 are cell cycle dependent. Our central hypothesis is that Cdc42 is differentially regulated at the cell ends by distinct cell-cycle-dependent cues to establish the cell polarization pattern. We will test this hypothesis by pursuing the following specific aims, [1] Determine how Cdc42 activation resumes at the cell ends in the G1/S phase; [2] Elucidate how a memory of growth from the previous cell cycle enables the pre-existing old end to initiate Cdc42 activation first; [3] Explain how the transition from monopolar to bipolar growth occur in G2 phase. With this project we expect to mechanistically understand how Cdc42 activation and associated growth patterns are modulated in different cell cycle stages. We will examine how signals from one cell cycle inform the growth pattern in the next generation. This will provide much needed insights into the principles that preserve polarized cell shape in complex systems. Due to the conserved nature of the proteins involved in this investigation, we expect that our findings will be relevant cell shape control in higher eukaryotes and provide potential therapeutic or diagnostic targets for diseases such as cancer.

项目摘要/摘要 极化的细胞在每个细胞周期中都保持其形状，这对它们的正常功能是必不可少的。异常情况 极化的细胞形态会导致癌症、代谢紊乱和组织完整性的丧失。在这里，我们将 研究一个长期存在的问题：细胞在每一轮分裂后如何始终如一地恢复其极性。 这项研究将使用分裂酵母，裂殖酵母庞贝模型系统进行 提供了许多具有良好特性的遗传工具来操纵影响细胞形状的保守蛋白质 在分组表决之后。CdC42是极化生长的主要调控因子。在分裂酵母中，细胞停止极化的CdC42 在有丝分裂期间，细胞末端的激活和随后的生长。分裂完成后，这些细胞结束 恢复CDC42激活和细胞生长。分裂后，cdc42的活化和极化生长总是 以单极方式从上一代预先存在的旧端恢复。单元格 当在G2期的新形成的细胞端处也恢复了CDC42的激活时，过渡到双极生长 对细胞周期的影响。我们的初步数据表明，在分裂后，CDC42在旧端恢复激活 而G2向双极激活的转变依赖于细胞周期。我们的中心假设是，镉42是 通过不同的细胞周期依赖的信号在细胞末端进行差异调节，以建立细胞极化 图案。我们将通过追求以下具体目标来检验这一假设，[1]确定CDC42如何 激活在G1/S阶段的细胞末端恢复；[2]解释从以前的生长记忆如何 细胞周期使预先存在的旧端能够首先启动CDC42激活；[3]解释如何从 G2期发生单极-双极生长。通过这个项目，我们希望机械地理解如何 CDC42的激活和相关的生长模式在不同的细胞周期阶段被调节。我们将研究 一个细胞周期的信号如何通知下一代的生长模式。这将提供急需的 对在复杂系统中保持极化细胞形状的原理的见解。由于自然界的保守 在这项研究中涉及的蛋白质中，我们预计我们的发现将与细胞形状控制相关 更高的真核细胞，并为癌症等疾病提供潜在的治疗或诊断靶点。