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

Abstract

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 G1 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 G2 phase of the mother cell, which controls the proliferation-quiescence decision in daughter cells and thereby couples protein production with cell proliferation.

EllipTrack: A Global-Local Cell-Tracking Pipeline for 2D Fluorescence Time-Lapse Microscopy

“…EllipTrack has already proved essential in two projects from our lab, enabling new discoveries about proliferation in both normal and cancer cells (Min et al, 2020;Yang et al, 2020). (C) Visualization of identified cell lineage as in Figure 1F, but by EllipTrack with the "Global" option.…”

Restriction point regulation at the crossroads between quiescence and cell proliferation

“…For cells entering the cell cycle from quiescence, signalling during G0/G1 results in commitment to a new round of division. However, for cycling cells it is clear that signalling during the previous cell cycle can be important for restriction point passage [89][90][91][92][93][94]. Early studies suggested that commitment decisions are solely made during G1, indicating that cells in a population begin the cell cycle all equally likely to divide [5,7,58].…”

“…As Cyclin D protein has a short half-life, any inheritance of previous mitogen exposure is likely mediated through CCND1 mRNA, which has a longer lifetime [94]. As Cyclin D protein levels are highly dependent on the global protein translation rate, which responds to mitogenic signalling through MAPK, the protein translation rate may also enable a form of cellular mitogenic memory [92]. In addition, endogenous DNA damage in mother cells can also influence proliferation-quiescence decisions in daughter cell cycles [98,99].…”

Restriction Point timing and cell cycle variability – a re-evaluation

“…The recent developments in live-cell imaging of cell cycle markers have brought renewed focus on cell cycle variability, with extensive data showing that ostensibly identical cells undergo critical transitions at widely differing cell ages [1][2][3][4][5][6][7][8][9][10][11][12]. Although such variability has long been recognised [13;14], the molecular basis for it remains poorly understood.…”