Temporal integration of mitogen history in mother cells controls proliferation of daughter cells

Multi-cellular organisms use mitogens to regulate cell proliferation, yet how fluctuating mitogenic signals are converted into proliferation-quiescence decisions is poorly understood. Here we combine live-cell imaging with temporally controlled perturbations to determine the timescale and mechanisms underlying the system. We identify a cellular memory-storage system that integrates mitogenic signals over long time periods to regulate proliferation rate. Contrary to the textbook model that cells only sense mitogen availability in G1, we find that mitogenic signaling is temporally integrated throughout the entire mother cell cycle, and that cells can detect and remember a one-hour lapse in mitogen signaling for over 12 hours. Protein translation rates serve as the integrator that proportionally converts mitogen history into corresponding levels of Cyclin D in G2 phase of the mother cell, which controls the proliferation-quiescence decision in daughter cells, and thereby couples protein production with cell proliferation.