Cytochrome P450 1A1 gene regulation by UVB involves crosstalk between the aryl hydrocarbon receptor and nuclear factor kappa B
2010 (English)In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 184, no 3, 466-473 p.Article in journal (Refereed) Published
UVB induces the expression of genes controlled by the aryl hydrocarbon receptor (AhR). a transcription factor that has been implicated in the UV stress response. In this study, we used the human hepatoma cell line HepG2 to investigate in more detail the effects of UVB irradiation on AhR activation and induction of cytochrome P450 1A1 (CYP1A1), a highly AhR-responsive gene. The CYP1A1 enzyme efficiently degrades 6-formylindolo[3,2-b]carbazole (FICZ), a high affinity ligand and suggested endogenous activator of the AhR. We show that physiologically relevant doses of UVB suppress CYP1A1 gene expression immediately after irradiation, but induce its expression later in an AhR-dependent manner. The initial repression phase of CYP1A1 transcription was mediated by another UVB-inducible transcription factor, the nuclear factor kappa B (NF kappa B). Crosstalk between AhR and NF kappa B signaling has earlier been implicated to control CYP1A1 expression following stimulation by xenobiotics and cytokines. Now, our findings clearly indicate a role of NF kappa B also in UVB-dependent AhR signaling. We also observed that UVB reduced the catalytic activity of the CYP1A1 enzyme. Thereby. UVB attenuated the clearance of FICZ, which led to prolonged AhR activation. We further noted that repeated irradiation with UVB or H2O2 treatment shifted the cells into a refractory state in which AhR signaling could not be efficiently activated by UVB or H2O2, but by ligands. Together, our results suggest that the NF kappa B-mediated initial suppression of CYP1A1 as well as the unresponsiveness of AhR signaling to repeated irradiation may be part of a protective cellular UV stress response.
Place, publisher, year, edition, pages
2010. Vol. 184, no 3, 466-473 p.
Aryl hydrocarbon receptor, UVB, Nuclear factor kappa B, Cytochrome P450 1A1, 6-formylindolo[3, 2-b]carbazole
Research subject Genetic Toxicology
IdentifiersURN: urn:nbn:se:su:diva-50131DOI: 10.1016/j.cbi.2010.01.038ISI: 000276920400019OAI: oai:DiVA.org:su-50131DiVA: diva2:380595
authorCount :52010-12-212010-12-212010-12-21Bibliographically approved