Regulation of Cell Cycle progression by the nuclear envelope

项目摘要/摘要 在生理条件下，细胞受到机械张力，从而触发多种信号。 途径和影响众多的细胞过程，包括细胞周期进程。众所周知， 这些张力敏感信号通路的功能障碍可导致不平衡的增殖和病理 组织重塑；然而，确切的分子途径仍然不清楚。当细胞经历紧张时， 由于其与细胞骨架的连接，细胞核经历了显著的形态变化 将机械力传递到核包层。我们最近证明，核扁平化可以激活 刺激G1/S转变的转录因子，导致我们假设核膜可以 作为张力传感器，其激活是细胞周期进程所必需的。基于这些发现， 以及其他人的工作，我们将通过应用生物物理学、成像、 以及生物化学方法来定义控制细胞周期进程的核张力敏感途径。 在目标1中，我们将确定RhoA介导的通路是否增加肌球蛋白的收缩能力和核 G1期间的包膜张力刺激G1/S的过渡。在目标2中，我们将把我们的调查扩展到 响应核紧张增加而触发的信号，我们将定义这些信号事件是如何 推动进入S阶段。在目标3中，我们将确定张力是否传递到原子核 间期刺激有丝分裂进程。我们预计，这一项目的成功完成将 加深我们对控制细胞周期进程和意志的张力敏感机制的理解 确定新的药物靶点以限制与过量相关的病理背景下的细胞增殖 肌动球蛋白张力。

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.