title: Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states.
abstract: Phenotypic heterogeneity within a population of genetically identical cells is emerging as a common theme in multiple biological systems, including human cell biology and cancer. Using live-cell imaging, flow cytometry, and kinetic modeling, we showed that two states--quiescence and cell cycling--can coexist within an isogenic population of human cells and resulted from low basal expression levels of p21, a Cyclin-dependent kinase (CDK) inhibitor (CKI). We attribute the p21-dependent heterogeneity in cell cycle activity to double-negative feedback regulation involving CDK2, p21, and E3 ubiquitin ligases. In support of this mechanism, analysis of cells at a point before cell cycle entry (i.e., before the G1/S transition) revealed a p21-CDK2 axis that determines quiescent and cycling cell states. Our findings suggest a mechanistic role for p21 in generating heterogeneity in both normal tissues and tumors.
authors.affiliation: Departments of Chemical Engineering and.
authors.forename: K Wesley
authors.initials: KW
authors.lastname: Overton
authors.affiliation: Chemical and Systems Biology, Stanford University, Stanford, CA 94305.
authors.forename: Sabrina L
authors.initials: SL
authors.lastname: Spencer
authors.affiliation: Departments of Chemical Engineering and.
authors.forename: William L
authors.initials: WL
authors.lastname: Noderer
authors.affiliation: Chemical and Systems Biology, Stanford University, Stanford, CA 94305.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Departments of Chemical Engineering and cliff.wang@stanford.edu.
authors.forename: Clifford L
authors.initials: CL
authors.lastname: Wang
mesh_terms: D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007700:Kinetics; D008239:Lysine / Q000378:metabolism; D008954:Models, Biological; D057054:Molecular Imaging; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D036341:Intercellular Signaling Peptides and Proteins; D044786:S-Phase Kinase-Associated Proteins; D001973:Bromodeoxyuridine; D008239:Lysine
keywords: cell dormancy; nongenetic cell heterogeneity; positive feedback loop; synthetic uORF; tumor heterogeneity