title: Inhibition of transcription results in accumulation of Wt p53 followed by delayed outburst of p53-inducible proteins: p53 as a sensor of transcriptional integrity.
abstract: Here we investigate activation of the p53 pathway by inhibition of transcription. Comparison of cells with either mutant p53 or wt p53 indicated that inhibition of p53- dependent transcription is necessary and sufficient for wt p53 accumulation. In addition to Mdm-2, p21 is required for effective p53 degradation. Transient inhibition of transcription resulted in initial downregulation of p21 and Mdm-2 leading to accumulation of wt p53. This was followed by induction of p21 and Mdm-2, normalization of p53 levels, and p21-dependent growth arrest. Although simultaneous induction of p53 and p21 could be detected by immunoblot, levels of p53 and p21 were discordant in individual cells. By inducing p21 and Mdm-2, p53 discriminates between transient and sustained inhibition of transcription. Transient inhibition results in p21-dependent growth, while sustained inhibition of transcription leads to p53-facilitated cell death. One can envision p53 as a physiological sensor of transcriptional integrity. Transient inhibition of p53- stimulated transcription by numerous stimuli including nucleotide depletion, hypoxia, UV light may be an prevalent mechanism of activation of wt p53 and its downstream pathways.
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. mikhailb@box-m.nih.gov
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Blagosklonny
authors.forename: Zoya N
authors.initials: ZN
authors.lastname: Demidenko
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D008297:Male; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004004:Dichlororibofuranosylbenzimidazole; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2