Regulation of Cell Cycle progression by the nuclear envelope

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.