Putting the brakes on the cell cycle: mechanisms of cellular growth arrest

Abstract

Precise regulation of cellular proliferation is critical to tissue homeostasis and development, but misregulation leads to diseases of excess proliferation or cell loss. To achieve precise control, cells utilize distinct mechanisms of growth arrest such as quiescence and senescence. The decision to enter these growth-arrested states or proliferate is mediated by the core cell-cycle machinery that responds to diverse external and internal signals. Recent advances have revealed the molecular underpinnings of these cell-cycle decisions, highlighting the unique nature of cell-cycle entry from quiescence, identifying endogenous DNA damage as a quiescence-inducing signal, and establishing how persistent arrest is achieved in senescence.

Figure 1:. Cell-Cycle Regulation in G1 phase.

Progression through the cell cycle depends upon the activation of cyclin-dependent kinases (CDK), whose activity requires the binding of specific regulatory subunits, known as cyclins. CDK4/6 is activated by the binding of D-type cyclins, whose expression are controlled by mitogenic growth factors. CDK2 is activated by E-type cyclins, known transcriptional targets of E2F. The activity of both CDK4/6 and CDK2 complexes are opposed by CIP/KIP CDK inhibitors, including p21, p27, and p57, while INK4 inhibitors like p16 exclusively bind CDK4/6, preventing cyclin D-CDK4/6 interaction. CDK activity promotes cell-cycle entry through the phosphorylation and inactivation of the transcriptional repressor, Rb. Following phosphorylation of Rb, E2F transcription is activated, promoting cell-cycle progression.

Figure 2:. Model for Integration of Cell-Cycle Inputs.

External and internal signals regulate the core cell-cycle machinery, including cyclins and CDK inhibitors. While mitogenic signals are known to regulate cyclin D expression, recent work has shown that endogenous DNA damage leads to the upregulation of p21. Additionally, extrinsic and intrinsic growth signals contribute to cell-cycle decisions. We propose a model in which the cell cycle decisions rely on the combined effects of pro-and anti-growth signals and their integration by their combined effects on the expression of CDKs, cyclins, and CDK inhibitors. This model is consistent with an ultrasensitive activation of CDKs.

Figure 3:. Comparing Senescence and Quiescence.

Contrary to the reversible nature of quiescence, senescence is a permanent growth arrest. Fundamental differences between these two types of growth arrest include continued high metabolism in senescent cells compared to the low metabolic state of quiescent cells. Moreover, senescent cells rely on p16 to inhibit CDK4/6, while quiescent cells utilize the CIP/KIP inhibitors to bind and inhibit CDK cyclin complexes.