title: Transient activation of p53 in G2 phase is sufficient to induce senescence.
abstract: DNA damage can result in a transient cell-cycle arrest or lead to permanent cell-cycle withdrawal. Here we show that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. This permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear retention of Cyclin B1. This rapid response is followed by the activation of the APC/C(Cdh1) (the anaphase-promoting complex/cyclosome and its coactivator Cdh1) several hours later. Inhibition of APC/C(Cdh1) activity fails to prevent cell-cycle withdrawal, whereas preventing nuclear retention of Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction of p53 in G2 cells is sufficient to induce senescence. Taken together, these results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear retention of Cyclin B1 as the first irreversible step in the onset of senescence.
authors.affiliation: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Lenno
authors.initials: L
authors.lastname: Krenning
authors.affiliation: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Femke M
authors.initials: FM
authors.lastname: Feringa
authors.affiliation: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Indra A
authors.initials: IA
authors.lastname: Shaltiel
authors.affiliation: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van den Berg
authors.affiliation: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: r.medema@nki.nl.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D021581:Active Transport, Cell Nucleus; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D016922:Cellular Senescence / Q000235:genetics*; D056744:Cyclin B1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004249:DNA Damage; D016195:G2 Phase; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
chemical_list: D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53