Molecular control of cell density-mediated exit to quiescence

Contact inhibition of cell proliferation regulates tissue size and prevents uncontrolled cell expansion. When cell density increases, contact inhibition can force proliferating cells into quiescence. Here we show that the variablememory of local cell density experienced by a mother cell controls the levels of the cyclin-dependent kinase (CDK) activator cyclin D1and inhibitor p27 innewborn daughters, which direct cells to proliferation or quiescence. Much of this regulation can be explained by rapid suppression of ERK activity by high cell density in mothers, which leads to lower cyclin D1 and higher p27 levels in daughters. Strikingly, cell density and mitogen signals compete by shifting the ratio of cyclin D1/p27 levels below or above a single sharp threshold that controls the proliferation decision. Thus, the history of competing cell density and mitogen signals experienced by mothers is funneled into a precise activator-inhibitor balance that decides the fate of daughter cells.

Automated summary

Cell density and mitogen signals compete to regulate the levels of cyclin D1 and p27, determining whether cells proliferate or enter quiescence. The history of competing signals experienced by mother cells is funneled into a precise activator-inhibitor balance that controls the fate of daughter cells.