The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit.
Tissue homeostasis in metazoans is regulated by transitions of cells between quiescence and proliferation. The hallmark of proliferating populations is progression through the cell cycle, which is driven by cyclin-dependent kinase (CDK) activity. Here, we introduce a live-cell sensor for CDK2 activity and unexpectedly found that proliferating cells bifurcate into two populations as they exit mitosis. Many cells immediately commit to the next cell cycle by building up CDK2 activity from an intermediate level, while other cells lack CDK2 activity and enter a transient state of quiescence. This bifurcation is directly controlled by the CDK inhibitor p21 and is regulated by mitogens during a restriction window at the end of the previous cell cycle. Thus, cells decide at the end of mitosis to either start the next cell cycle by immediately building up CDK2 activity or to enter a transient G0-like state by suppressing CDK2 activity.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: spencer1@stanford.edu.
Sabrina L
SL
Spencer
Steven D
SD
Cappell
Feng-Chiao
FC
Tsai
K Wesley
KW
Overton
Clifford L
CL
Wang
Tobias
T
Meyer
D016475:3T3 Cells; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008938:Mitosis; D016160:Retinoblastoma Protein / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2