title: Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway.
abstract: Cytochrome P450 1B1 (CYP1B1) is an enzyme that has a unique tumor-specific pattern of expression and is capable of bioactivating a wide range of carcinogenic compounds. We have reported previously that coordinated upregulation of CYP1B1 by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and the aryl hydrocarbon receptor ligands, may increase bioactivation of promutagens, such as benzo[a]pyrene (BaP) in epithelial cells. Here, we extend those studies by describing a novel mechanism participating in the regulation of CYP1B1 expression, which involves activation of the p38 mitogen-activated protein kinase (p38) and mitogen- and stress-activated protein kinase 1 (MSK1). Using inhibitors of p38 and MSKs, as well as mouse embryonic cells derived from p38α-deficient and MSK1/2 double knockout mice, we show here that TNF-α potentiates CYP1B1 upregulation via the p38/MSK1 kinase cascade. Effects of this inflammatory cytokine on CYP1B1 expression further involve the positive transcription elongation factor b (P-TEFb). The inhibition of the P-TEFb subunit, cyclin-dependent kinase 9 (CDK9), which phosphorylates RNA polymerase II (RNAPII), prevented the enhanced CYP1B1 induction by a combination of BaP and inflammatory cytokine. Furthermore, using chromatin immunoprecipitation assays, we found that cotreatment of epithelial cells with TNF-α and BaP resulted in enhanced recruitment of both CDK9 and RNAPII to the Cyp1b1 gene promoter. Overall, these results have implications concerning the contribution of inflammatory factors to carcinogenesis, since enhanced CYP1B1 induction during inflammation may alter metabolism of exogenous carcinogens, as well as endogenous CYP1B1 substrates playing role in tumor development.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno 62165, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Smerdová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno 62165, Czech Republic, Institute of Experimental Biology, Faculty of Science, Brno 61137, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Šmerdová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno 62165, Czech Republic, Institute of Experimental Biology, Faculty of Science, Brno 61137, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Kabátková
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Brno 62100, Czech Republic and.
authors.forename: Jiří
authors.initials: J
authors.lastname: Kohoutek
authors.affiliation: Central European Institute of Technology (CEITEC), Masaryk University, Brno 62500, Czech Republic.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Blažek
authors.affiliation: Department of Chemistry and Toxicology, Veterinary Research Institute, Brno 62100, Czech Republic and.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno 62165, Czech Republic, vondracek@ibp.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Vondráček
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics*; D002273:Carcinogens / Q000633:toxicity; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1 / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D002273:Carcinogens; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D048051:p38 Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II