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@article{1202850, author = {Šmerdová, Lenka and Svobodová, Jana and Kabátková, Markéta and Kohoutek, Jiří and Blažek, Dalibor and Machala, Miroslav and Vondráček, Jan}, article_location = {Oxford}, article_number = {11}, doi = {http://dx.doi.org/10.1093/carcin/bgu190}, keywords = {CYP1B1; inflammation; p38 MAP kinase; MSK; metabolism of carcinogens}, language = {eng}, issn = {0143-3334}, journal = {Carcinogenesis}, title = {Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway}, url = {http://www.ncbi.nlm.nih.gov/pubmed/25233930}, volume = {35}, year = {2014} }
TY - JOUR ID - 1202850 AU - Šmerdová, Lenka - Svobodová, Jana - Kabátková, Markéta - Kohoutek, Jiří - Blažek, Dalibor - Machala, Miroslav - Vondráček, Jan PY - 2014 TI - Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway JF - Carcinogenesis VL - 35 IS - 11 SP - 2534-2543 EP - 2534-2543 PB - Oxford University Press SN - 01433334 KW - CYP1B1 KW - inflammation KW - p38 MAP kinase KW - MSK KW - metabolism of carcinogens UR - http://www.ncbi.nlm.nih.gov/pubmed/25233930 L2 - http://www.ncbi.nlm.nih.gov/pubmed/25233930 N2 - 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-delta(TNF-delta) 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 p38delta-deficient and MSK1/2 double knockout mice, we show here that TNF-delta 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-delta 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 ER -
ŠMERDOVÁ, Lenka, Jana SVOBODOVÁ, Markéta KABÁTKOVÁ, Jiří KOHOUTEK, Dalibor BLAŽEK, Miroslav MACHALA and Jan VONDRÁČEK. Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway. \textit{Carcinogenesis}. Oxford: Oxford University Press, 2014, vol.~35, No~11, p.~2534-2543. ISSN~0143-3334. Available from: https://dx.doi.org/10.1093/carcin/bgu190.
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