Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25233930
DOI
10.1093/carcin/bgu190
PII: bgu190
Knihovny.cz E-resources
- MeSH
- Cyclin-Dependent Kinase 9 genetics MeSH
- Cytochrome P-450 CYP1B1 biosynthesis genetics MeSH
- Cytokines metabolism MeSH
- Carcinogenesis drug effects genetics MeSH
- Carcinogens toxicity MeSH
- Humans MeSH
- p38 Mitogen-Activated Protein Kinases antagonists & inhibitors genetics metabolism MeSH
- Mice MeSH
- Neoplasms chemically induced genetics pathology MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- RNA Polymerase II genetics MeSH
- Signal Transduction drug effects MeSH
- Tumor Necrosis Factor-alpha metabolism MeSH
- Positive Transcriptional Elongation Factor B genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CDK9 protein, human MeSH Browser
- Cyclin-Dependent Kinase 9 MeSH
- Cyp1b1 protein, mouse MeSH Browser
- Cytochrome P-450 CYP1B1 MeSH
- Cytokines MeSH
- Carcinogens MeSH
- p38 Mitogen-Activated Protein Kinases MeSH
- RNA Polymerase II MeSH
- Tumor Necrosis Factor-alpha MeSH
- Positive Transcriptional Elongation Factor B MeSH
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.
Central European Institute of Technology Masaryk University Brno 62500 Czech Republic
Department of Chemistry and Toxicology Veterinary Research Institute Brno 62100 Czech Republic and
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