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 variable memory of local cell density experienced by a mother cell controls the levels of the cyclin-dependent kinase (CDK) activator cyclin D1 and inhibitor p27 in newborn 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. [Display omitted] • Memory of local cell density from mother cells regulates proliferation in daughters • Memory of local cell density shifts the expression ratio of cyclin D1 over p27 • The cyclin D1-p27 balance controls proliferation in an ultrasensitive manner • Competing cell density and mitogen signals converge on the cyclin D1-p27 balance Using live single-cell microscopy, Fan and Meyer show that the decision of newborn daughter cells to proliferate or become quiescent is controlled by the memory of local cell density inherited from mother cells. This memory is mediated by an ultrasensitive activator-inhibitor balance between cyclin D1 and p27. [ABSTRACT FROM AUTHOR]