title: Activation of p53 in Human and Murine Cells by DNA-Damaging Agents Differentially Regulates Aryl Hydrocarbon Receptor Levels.
abstract: Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates multiple cellular processes. The anticancer drug doxorubicin (DOX) can activate AhR-mediated transcription of target genes. Because DOX in cells activates a DNA damage response involving ataxia telangiectasia-mutated (ATM)-mediated activation of p53, we investigated whether the activation of the p53 in cells by DNA-damaging agents such as DOX or bleomycin could regulate the AhR levels. Here we report that activation of p53 by DNA-damaging agents in human cells increased levels of AhR through a posttranscriptional mechanism. Accordingly, fibroblasts from ATM patients, which are defective in p53 activation, expressed reduced constitutive levels of AhR and treatment of cells with bleomycin did not appreciably increase the AhR levels. Further, activation of p53 in cells stimulated the expression of AhR target genes. In murine cells, activation of p53 reduced the levels of AhR messenger RNA and protein and reduced the expression of AhR target genes. Our observations revealed that activation of p53 in human and murine cells differentially regulates AhR levels.
authors: Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA Department of Research Cincinnati VA Medical Center, Cincinnati, OH, USA.
authors: Ravichandran
authors: R
authors: Panchanathan
authors: Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA Department of Research Cincinnati VA Medical Center, Cincinnati, OH, USA.
authors: Hongzhu
authors: H
authors: Liu
authors: Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA Department of Research Cincinnati VA Medical Center, Cincinnati, OH, USA divaker.choubey@uc.edu.
authors: Divaker
authors: D
authors: Choubey
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009153:Mutagens / Q000633:toxicity*; D050505:Mutant Proteins / Q000819:agonists / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D013723:Teratogens / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D051792:Basic Helix-Loop-Helix Proteins; D008024:Ligands; D009153:Mutagens; D050505:Mutant Proteins; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; C111235:AHR protein, human; C484722:Ahr protein, mouse; C495901:TP53 protein, human
keywords: ATM; DNA damage; aryl hydrocarbon receptor; cancer therapy; p53