Regulation of Cell Cycle progression by the nuclear envelope

核膜对细胞周期进程的调节

• 批准号: 10659597
• 负责人: Christophe Daniel Guilluy
• 金额: $ 32.67万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659597
• 关键词: Acceleration; Actomyosin; Address; Anaphase; Biochemical; Biophysics; Calcium; Cardiovascular Diseases; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Complex; Cytoskeleton; Disease; Event; Fibrosis; Filament; Functional disorder; Future; G1/S Transition; Gene Expression; Grant; Growth; Homeostasis; Image; Interphase; Investigation; Malignant Neoplasms; Mechanics; Mediating; Metaphase; Mitosis; Mitotic spindle; Molecular; Morphology; Normal Cell; Nuclear; Nuclear Envelope; Pathogenesis; Pathologic; Pathway interactions; Physiological; Process; Proliferating; Proteomics; S phase; Signal Pathway; Signal Transduction; Stimulus; Testing; Tissues; Transcription Factor AP-1; Up-Regulation; Work; biophysical tools; experience; innovation; mechanical force; mechanotransduction; pharmacologic; public health relevance; response; sensor; spatiotemporal; transcription factor; transmission process

PROJECT SUMMARY/ABSTRACT Under physiological conditions, cells are subjected to mechanical tension that triggers multiple signaling pathways and impacts numerous cellular processes, including cell cycle progression. It is well established that a dysfunction of these tension-sensitive signaling pathways can cause unbalanced proliferation and pathological tissue remodeling; however, the precise molecular pathways remain poorly defined. As cells experience tension, the nucleus undergoes significant morphological changes due to its connection with the cytoskeleton that transmits mechanical force to the nuclear envelope. We recently showed that nuclear flattening activates transcription factors that stimulate G1/S transition, leading us to hypothesize that the nuclear membrane could serve as a tension sensor whose activation is necessary for cell cycle progression. Building on these findings, as well as on the work of others, we will test this hypothesis by applying a combination of biophysics, imaging, and biochemical approaches to define the nuclear tension-sensitive pathways that control cell cycle progression. In Aim #1, we will determine whether RhoA-mediated pathways increase actomyosin contractility and nuclear envelope tension during G1 to stimulate G1/S transition. In Aim#2, we will extend our investigation to the signaling triggered in response to an increase in nuclear tension and we will define how these signaling events promote entry into S phase. In Aim#3, we will determine whether tension transmitted to the nucleus during interphase stimulates mitosis progression. We anticipate that the successful completion of this project will increase our understanding of the tension-sensitive mechanisms controlling cell cycle progression and will identify new pharmacological targets to limit cell proliferation in pathological contexts associated with excessive actomyosin tension.

项目摘要/摘要 在生理条件下，细胞会受到机械张力，从而触发多个信号传导 途径并影响许多细胞过程，包括细胞周期进程。已经确定了 这些对张力敏感的信号通路的功能障碍会导致不平衡的增殖和病理 组织重塑；但是，精确的分子途径仍然很差。随着细胞的张力， 由于其与细胞骨架有关，因此经历了显着的形态变化 将机械力传输到核包膜。我们最近表明，核扁平化激活 刺激G1/s过渡的转录因子，导致我们假设核膜可以 用作张力传感器，其激活对于细胞周期进程是必需的。以这些发现为基础 除了他人的工作外，我们还将通过应用生物物理学，成像，， 以及定义控制细胞周期进程的核张力敏感途径的生化方法。 在AIM＃1中，我们将确定Rhoa介导的途径是否增加了肌球蛋白的收缩力和核 G1期间的包膜张力刺激G1/s转变。在AIM＃2中，我们将把调查扩展到 响应核张力的增加而触发的信号传导，我们将定义这些信号事件如何 促进进入S阶段。在AIM＃3中，我们将确定是否在 间相刺激有丝分裂进展。我们预计该项目的成功完成将 增加我们对控制细胞周期进程的张力敏感机制的理解，并将 确定新的药理学靶标，以限制与过度相关的病理环境中的细胞增殖 肌动球蛋白张力。