Fig. 6: Cell growth and proliferation are tightly regulated and correlate with p38- and p53-signaling states.

A A model demonstrating how sensing of cell size can affect both cell growth and proliferation to keep homeostasis of cell size. B Scatter plot showing the initial and long-term effects of rapamycin or SNS-032 on the average cellular growth rate and division rate of Rpe1 cells. Data points indicate the average growth and division rates measured: (1) during the first 24 h of drug treatment and (2) during 24–60 h of drug treatment. C Average growth rate vs. division rate in five cell lines (Rpe1, HeLa, U2OS, SAOS2, 16HBE) treated with either growth inhibitors (red) or cdk1/2 inhibitors (blue). Measurements in each cell line were normalized by the values measured for untreated control samples (gray) of the same cell line. The growth inhibitors used were: Cycloheximide, Torin-2, and Rapamycin, at varying doses (de- tailed in “Methods”). The cdk1/2 inhibitors used were: SNS-032, PHA848125, Cdk2 Inhibitor III, and Dinaciclib, at varying doses (detailed in “Methods”). D, E The average cell size for a given drug correlated with its PC1 value calculated on the reporters’ activity for data from Kaufman et al. (D) and Liu at al. (E). F Average growth rate vs. division rate for A375 cells in Signalome screen. Each circle represents one screened condition (drug treatment). The circle’s color indicates the value of PC1 in that condition. Contour lines show the average value of PC1 as a function of growth rate and division rate. G The average level of p38 (top) and p53 (bottom) activity as a function of growth rate and cell cycle length. H A model proposing how drugs which affect cell division activate the p53-signaling state while drugs that affect cell growth activate the p38-signaling state. Each state in return actives a compensation mechanism resulting in a new equilibrium. Source data are provided with this paper.