Department of Biochemistry and BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80303, USA.
Science. 2020 Jun 12;368(6496):1261-1265. doi: 10.1126/science.aay8241. Epub 2020 Apr 2.
Multicellular organisms use mitogens to regulate cell proliferation, but how fluctuating mitogenic signals are converted into proliferation-quiescence decisions is poorly understood. In this work, we combined live-cell imaging with temporally controlled perturbations to determine the time scale and mechanisms underlying this system in human cells. Contrary to the textbook model that cells sense mitogen availability only in the G cell cycle phase, we find that mitogenic signaling is temporally integrated throughout the entire mother cell cycle and that even a 1-hour lapse in mitogen signaling can influence cell proliferation more than 12 hours later. Protein translation rates serve as the integrator that proportionally converts mitogen history into corresponding levels of cyclin D in the G phase of the mother cell, which controls the proliferation-quiescence decision in daughter cells and thereby couples protein production with cell proliferation.
多细胞生物利用有丝分裂原来调节细胞增殖，但有丝分裂原信号如何波动转化为增殖-静止的决策，目前还知之甚少。在这项工作中，我们结合了活细胞成像和时间控制的扰动，以确定人类细胞中该系统的时间尺度和机制。与细胞仅在 G 细胞周期阶段感知有丝分裂原可用性的教科书模型相反，我们发现有丝分裂原信号在整个母细胞周期中是时间整合的，即使有 1 小时的有丝分裂原信号中断，也会在 12 小时后对细胞增殖产生超过 1 小时的影响。蛋白质翻译率作为整合器，将有丝分裂原的历史以比例的方式转化为母细胞 G 期的细胞周期蛋白 D 的相应水平，从而控制子细胞的增殖-静止决策，并将蛋白质合成与细胞增殖联系起来。
