CDK2 activity dictates whether cells commit to a next cell cycle or become quiescent.

  • Major finding: CDK2 activity dictates whether cells commit to a next cell cycle or become quiescent.

  • Approach: A fluorescence-based sensor of CDK2 activity allowed single-cell analysis in cycling cells.

  • Impact: Cells commit to a subsequent cell cycle at a restriction point at the end of the previous cell cycle.

Reversible transitions between proliferative and quiescent cellular states are critical for tissue homeostasis, but the mechanisms underlying cell-cycle commitment are poorly understood. Cells are believed to cross a “restriction point” sometime in late G1 in association with increased cyclin-dependent kinase 2 (CDK2) activity, at which point they are committed to completion of the cell cycle. However, commitment mechanisms may be altered in the mitogen-starved or synchronized cells used in most cell-cycle studies. Spencer and colleagues developed a technique to analyze cell-cycle commitment in single cells within asynchronous, proliferating human cell populations using localization of a fluorescently labeled peptide that is spatially regulated by CDK2 as a readout of CDK2 activity. Unexpectedly, soon after anaphase, two distinct cell populations emerged: a population with increasing CDK2 activity that immediately continued to a next cell cycle, and a population with low CDK2 activity that entered a transient quiescent state. CDK2 activity after mitosis was dependent on endogenous levels of the CDK inhibitor p21, with elevated levels of p21 triggering entry into the low-CDK2 quiescent state. Cells with increasing CDK2 activity after mitotic exit were committed to completing the next cell cycle regardless of the presence of mitogenic stimuli or MEK activity, whereas low-CDK2 cells did not re-enter the cell cycle unless mitogens were present. These findings imply that the primary mitogen-dependent restriction point actually occurs before M phase, and a second mitogen-dependent restriction point is only a feature of CDK2-low cells that enter a G0-like state immediately after M phase. Additional single-cell studies in cycling cell populations may further refine our understanding of the cell cycle.

Spencer SL, Cappell SD, Tsai FC, Overton KW, Wang CL, Meyer T. The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 2013 Sept 26 [Epub ahead of print].