Cell-cycle-dependent cell polarity control

细胞周期依赖性细胞极性控制

• 批准号: 10112928
• 负责人: Maitreyi Das
• 金额: $ 29.79万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 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/10112928
• 关键词: Biological Models; Cell Cycle; Cell Cycle Stage; Cell Maintenance; Cell Polarity; Cell Shape; Cell division; Cells; Cellular biology; Chemicals; Complex; Cues; Cyclin B; Cytokinesis; Data; Development; Diagnostic; Disease; Eukaryota; Fission Yeast; G1 Arrest; G1 Phase; G2 Phase; Generations; Genetic; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Investigation; Lead; Malignant Neoplasms; Membrane Proteins; Memory; Metabolic Diseases; Mitosis; Mitotic; Nature; Neurons; Normal Cell; Oranges; Organism; Pattern; Phase; Property; Proteins; Regulation; Rod; Shapes; Signal Transduction; Site; System; Testing; Therapeutic; Tissues; base; cell growth; insight; live cell imaging; mathematical model; next generation; novel diagnostics; novel therapeutics; polarized cell; preservation; recruit; response; tool; yeast genetics

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.

项目总结/摘要 极化细胞在每个细胞周期中保持其形状，这对它们的正常功能至关重要。异常 在极化细胞形状中，可导致癌症、代谢紊乱和组织完整性丧失。在这里，我们将 研究一个长期存在的问题，即细胞如何在每一轮分裂后始终恢复其极性。 本研究将使用裂殖酵母、粟酒裂殖酵母模型系统进行， 提供了许多良好表征的遗传工具来操纵影响细胞形状的保守蛋白质 在分裂之后。cdc 42是极化生长的主要调节因子。在裂变酵母中，细胞停止极化Cdc 42 在有丝分裂过程中细胞末端的活化和随后的生长。分裂完成后，这些细胞结束 恢复Cdc 42活化和细胞生长。细胞分裂后，Cdc 42的激活和极化生长总是 以单极方式从上一代中预先存在的旧端恢复。细胞 当Cdc 42激活也在G2期的新形成细胞末端恢复时， 细胞周期。我们的初步数据表明，分裂后Cdc 42在旧端的激活恢复， G2期向双极活化的转变依赖于细胞周期。我们的中心假设是Cdc 42是 通过不同的细胞周期依赖性线索在细胞末端进行差异调节，以建立细胞极化 格局我们将通过追求以下具体目标来测试这一假设，[1]确定Cdc 42 在G1/S期细胞结束时激活恢复; [2]阐明如何从以前的生长记忆 细胞周期使预先存在的老端首先启动Cdc 42激活; [3]解释如何从 G2期为单极-双极生长。通过这个项目，我们希望机械地了解如何 cdc 42的激活和相关的生长模式在不同的细胞周期阶段受到调节。我们将研究 一个细胞周期的信号如何告知下一代的生长模式。这将提供急需的 深入了解在复杂系统中保持极化细胞形状的原理。由于保守的性质， 在这项研究中涉及的蛋白质，我们希望我们的发现将是相关的细胞形状控制， 高等真核生物，并为疾病如癌症提供潜在的治疗或诊断靶点。