Cytochrome P450 1A1 gene regulation by UVB involves crosstalk between the aryl hydrocarbon receptor and nuclear factor kappaB.
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 kappaB (NFkappaB). Crosstalk between AhR and NFkappaB signaling has earlier been implicated to control CYP1A1 expression following stimulation by xenobiotics and cytokines. Now, our findings clearly indicate a role of NFkappaB 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 H(2)O(2) treatment shifted the cells into a refractory state in which AhR signaling could not be efficiently activated by UVB or H(2)O(2), but by ligands. Together, our results suggest that the NFkappaB-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.
Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, S-17177 Stockholm, Sweden.
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S
Luecke
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Wincent
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M
Backlund
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U
Rannug
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Rannug
D002227:Carbazoles / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction; D014466:Ultraviolet Rays; D015854:Up-Regulation
C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D016328:NF-kappa B; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1