title: p53 protein accumulation in addition to the transactivation activity is required for p53-dependent cell cycle arrest after treatment of cells with camptothecin.
abstract: In this study we characterize the connections between p53-dependent G1 cell cycle arrest, transcriptional activation of the protein and the increase of its intracellular steady-state concentration. Several cell lines expressing wild-type p53 protein were treated with increasing concentrations of DNA-damaging drug camptothecin. Lower doses of the drug caused transcriptional activation of p53, but no accumulation of the protein was detected. Only after a certain threshold dose of camptothecin does the amount of the protein rapidly increase and reach its plateau levels. The threshold dose was different for different cell lines, but the general non-linear profile was similar. Increase of p53 level was accompanied by additional transcriptional activation of some p53 target genes (i.e. waf1), but not the others (mdm2). We demonstrate here that transcriptional activation of p53 after the treatment of camptothecin is not sufficient to cause p53-dependent G1 cell cycle arrest. The latter is observable only after the increase of steady-state level of p53. Low drug concentrations, although accompanied by transcriptional activation of p53, do not cause either p53 protein accumulation nor cell cycle arrest at G1. We propose a model for p53 acting as a part of cellular sensor system detecting the severity of DNA damage.
authors: Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Riia23, Tartu, 51010, Estonia.
authors: V
authors: V
authors: Jaks
authors: A
authors: A
authors: Jõers
authors: A
authors: A
authors: Kristjuhan
authors: T
authors: T
authors: Maimets
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000737:chemistry; D002166:Camptothecin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D004261:DNA Replication; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D051379:Mice; D016133:Polymerase Chain Reaction; D016196:S Phase; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014764:Viral Proteins
chemical_list: D000970:Antineoplastic Agents; C534702:CCNG1 protein, human; C493956:CDKN1A protein, human; C534703:Ccng1 protein, mouse; C493957:Cdkn1a protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C062210:bacteriophage T7 RNA polymerase; D012321:DNA-Directed RNA Polymerases; D001973:Bromodeoxyuridine; D002166:Camptothecin