FIGURE 2.

A model for mammalian cell size control. (A) Cell size regulation shares similar control circuits as a thermostat that controls the temperature of a room. Note that analogies between circuit components are based on the direction of regulation, i.e., faster cell division/cell cycle alone reduces cell size (turning on/up the air conditioner reduces room temperature), and faster cell growth alone increases cell size (turning on/up the furnace increases room temperature). Left panel: A thermometer measures the temperature of the room and compares it to the setpoint determined by the dial. If the room temperature is lower than the setpoint, the thermostat turns on the furnace and turns off the air conditioner to heat up the room. Conversely, if the room temperature is higher than the setpoint, the thermostat turns off the furnace and turns on the air conditioner to cool the room down. This dual-arm negative feedback regulation on the furnace and air conditioner maintains the room temperature at the setpoint. Right panel: Cell size control may involve a cell size sensor, relating a cell’s actual size with a “programmed” target size value, to regulate cell cycle progression (① cell size checkpoint) and cellular growth (② size-dependent regulation of growth rate), respectively. Cells that are smaller than their target size mainly compensate with a longer cell cycle mediated by size-dependent G1 extension, whereas cells that are larger than their target size mainly compensate with slowed cell growth, mediated by the upregulation of global protein degradation. This dual-arm negative feedback regulation on cell cycle and cellular growth maintains cell size relatively stable at the target size value. (B) With a properly functional size control mechanism (e.g., cell size checkpoint), small cells compensate with a longer period of growth in G1, allowing all cells to reach similar sizes at S phase entry. (C) When the homeostatic size control is perturbed (e.g., p38 inhibition, Rb1 knockout), cells would fail to compensate for their small size with a G1 extension, resulting in increased size heterogeneity. (D) When the target size is changed to a different level without perturbing the homeostatic control mechanism, cell size is shifted to the new setpoint while maintaining the compensatory G1 extension (e.g., CDK4 inhibition). Diagrams created using BioRender.com.