Inhibition of transcription results in accumulation of Wt p53 followed by delayed outburst of p53-inducible proteins: p53 as a sensor of transcriptional integrity.
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.
Blagosklonny
Mikhail V
MV
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. mikhailb@box-m.nih.gov
Demidenko
Zoya N
ZN
Fojo
Tito
T
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*
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