Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal

Abstract

In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle1,2, when mitogen signalling engages a positive feedback loop between cyclin A2/cyclin-dependent kinase 2 (CDK2) and the retinoblastoma protein3–5. Contrary to this textbook model, here we show that the decision to proliferate is actually fully reversible. Instead, we find that all cycling cells will exit the cell cycle in the absence of mitogens unless they make it to mitosis and divide first. This temporal competition between two fates, mitosis and cell cycle exit, arises because cyclin A2/CDK2 activity depends upon CDK4/6 activity throughout the cell cycle, not just in G1 phase. Without mitogens, mitosis is only observed when the half-life of cyclin A2 protein is long enough to sustain CDK2 activity throughout G2/M. Thus, cells are dependent on mitogens and CDK4/6 activity to maintain CDK2 activity and retinoblastoma protein phosphorylation throughout interphase. Consequently, even a 2-h delay in a cell’s progression towards mitosis can induce cell cycle exit if mitogen signalling is lost. Our results uncover the molecular mechanism underlying the restriction point phenomenon, reveal an unexpected role for CDK4/6 activity in S and G2 phases and explain the behaviour of all cells following loss of mitogen signalling.

CDK4/6 activity is required during G 2 arrest to prevent stress-induced endoreplication

“…5). These findings are in line with a recent report indicating that loss of CDK4/6 activity in S-G 2 leads to G 2 cell cycle exit ( 42 ). Together, this work indicates that the CDK2-Rb positive feedback loop is not self-sustaining during G 2 arrest, much as it is not self-sustaining in G 1 ( 43 ).…”

G1 Dynamics at the Crossroads of Pluripotency and Cancer

“…High CDK2 activity initiates a CDK2-Rb positive feedback that drives cell cycle progression independently of CDK4/6 activity [ 36 ]. However, recent studies indicate that persistent CDK4/6 activity can be required to maintain both Rb hyperphosphorylation throughout all of G1 phase [ 37 , 38 ], and CDK2 activity in S and G2 phases [ 39 ]. Different models for the regulation of the CDK-Rb-E2F pathway and G1/S progression are presented in this excellent review [ 40 ].…”

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets

“…Recent research has expanded the understanding of cell cycle control. Cells depend on sustained mitogen signaling and CDK4/6 activity to maintain CDK2 activity and Rb protein phosphorylation in a feed-forward loop, demonstrating that until mitosis, the decision to proliferate is reversible . The temporal integration of mitogenic signaling throughout the mother cell cycle can influence the daughter cell proliferation .…”

“…Cells depend on sustained mitogen signaling and CDK4/6 activity to maintain CDK2 activity and Rb protein phosphorylation in a feed-forward loop, demonstrating that until mitosis, the decision to proliferate is reversible. 5 The temporal integration of mitogenic signaling throughout the mother cell cycle can influence the daughter cell proliferation. 6 These findings extend significantly the understanding of cell cycle commitment beyond the textbook model and suggest that the strength and duration of the mitogen signal have a profound influence not only on cell cycle commitment but also on the fate of the daughter cells.…”