Acetylation of p53 stimulates miRNA processing and determines cell survival following genotoxic stress
Copyright policy )Acetylation of p53 stimulates miRNA processing and determines cell survival following genotoxic stress
It is widely accepted that different forms of stress activate a common target, p53, yet different outcomes are triggered in a stress-specific manner. For example, activation of p53 by genotoxic agents, such as camptothecin (CPT), triggers apoptosis, while non-genotoxic activation of p53 by Nutlin-3 (Nut3) leads to cell-cycle arrest without significant apoptosis. Such stimulus-specific responses are attributed to differential transcriptional activation of various promoters by p53. In this study, we demonstrate that CPT, but not Nut3, induces miR-203, which downregulates anti-apoptotic bcl-w and promotes cell death in a p53-dependent manner. We find that acetylation of K120 in the DNA-binding domain of p53 augments its association with the Drosha microprocessor and promotes nuclear primary miRNA processing. Knockdown of human orthologue of Males absent On the First (hMOF), the acetyltransferase that targets K120 in p53, abolishes induction of miR-203 and cell death mediated by CPT. Thus, this study reveals that p53 acetylation at K120 plays a critical role in the regulation of the Drosha microprocessor and that post-transcriptional regulation of gene expression by p53 via miRNAs plays a role in determining stress-specific cellular outcomes.
- University of California, San Francisco United States
- Kingâs University United States
- Tufts University United States
- Molecular Research Institute United States
- Tufts Medical Center United States
Piperazines (mesh), p53, Ribonuclease III, Biomedical and clinical sciences, Imidazoles (mesh), Post-Transcriptional, Camptothecin (mesh), Cell Survival (mesh), 11 Medical and Health Sciences (for), Medical and Health Sciences, Piperazines, 31 Biological sciences (for-2020), 2.1 Biological and endogenous factors, Apoptosis Regulatory Proteins (mesh), RNA Processing, Post-Transcriptional, Promoter Regions, Genetic, Developmental Biology (science-metrix), Histone Acetyltransferases, HCT116 Cells (mesh), Humans (mesh), apoptosis, Imidazoles, Acetylation, Biological Sciences, 06 Biological Sciences (for), Post-Transcriptional (mesh), Biotechnology, Ribonuclease III (mesh), 570, RNA Processing, Cell Survival, 610, 08 Information and Computing Sciences (for), Biotechnology (rcdc), DNA Damage (mesh), Acetylation (mesh), Drosha, MicroRNAs (mesh), Promoter Regions, Genetic, Information and Computing Sciences, Genetics, Humans, Histone Acetyltransferases (mesh), miRNA, 31 Biological Sciences (for-2020), Genetics (rcdc), Tumor Suppressor Protein p53 (mesh), 2.1 Biological and endogenous factors (hrcs-rac), HCT116 Cells, 3101 Biochemistry and Cell Biology (for-2020), MicroRNAs, 32 Biomedical and clinical sciences (for-2020), Genetic (mesh), Camptothecin, Biochemistry and Cell Biology, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, Developmental Biology, DNA Damage
Piperazines (mesh), p53, Ribonuclease III, Biomedical and clinical sciences, Imidazoles (mesh), Post-Transcriptional, Camptothecin (mesh), Cell Survival (mesh), 11 Medical and Health Sciences (for), Medical and Health Sciences, Piperazines, 31 Biological sciences (for-2020), 2.1 Biological and endogenous factors, Apoptosis Regulatory Proteins (mesh), RNA Processing, Post-Transcriptional, Promoter Regions, Genetic, Developmental Biology (science-metrix), Histone Acetyltransferases, HCT116 Cells (mesh), Humans (mesh), apoptosis, Imidazoles, Acetylation, Biological Sciences, 06 Biological Sciences (for), Post-Transcriptional (mesh), Biotechnology, Ribonuclease III (mesh), 570, RNA Processing, Cell Survival, 610, 08 Information and Computing Sciences (for), Biotechnology (rcdc), DNA Damage (mesh), Acetylation (mesh), Drosha, MicroRNAs (mesh), Promoter Regions, Genetic, Information and Computing Sciences, Genetics, Humans, Histone Acetyltransferases (mesh), miRNA, 31 Biological Sciences (for-2020), Genetics (rcdc), Tumor Suppressor Protein p53 (mesh), 2.1 Biological and endogenous factors (hrcs-rac), HCT116 Cells, 3101 Biochemistry and Cell Biology (for-2020), MicroRNAs, 32 Biomedical and clinical sciences (for-2020), Genetic (mesh), Camptothecin, Biochemistry and Cell Biology, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, Developmental Biology, DNA Damage
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