Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway

Publikace: CARCINOGENESIS 35, 2534-2543 Autoři: Smerdova, L., Svobodova, J., Kabatkova, M., Kohoutek, J., Blazek, D., Machala, M., Vondracek, J. Rok: 2014

Abstrakt

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-alpha (TNF-alpha) 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 (MSKI). Using inhibitors of p38 and MSKs, as well as mouse embryonic cells derived from p38 alpha-deficient and MSK1/2 double knockout mice, we show here that TNF-alpha potentiates CYPIRI upregulation via the p38/MSK1 kinase cascade. Effects of this inflammatory cytokine on CYPIBI 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 H (RNAPII), prevented the enhanced CYP1B1 induction by a combination of RaP and inflammatory cytokine. Furthermore, using chromatin immunoprecipitation assays, we found that cotreatment of epithelial cells with TNE-alpha 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.