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Carcinogenesis, Vol. 21, No. 12, 2267-2274, December 2000
© 2000 Oxford University Press

CARCINOGENESIS

Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway

Christoph Vogel, Anne-Marie J.F. Boerboom, Claudia Baechle, Claudia El-Bahay1, Regine Kahl1, Gisela H. Degen2 and Josef Abel3

Department of Experimental Toxicology, Medical Institute of Environmental Hygiene at the Heinrich-Heine-University, 40225 Duesseldorf,
1 Institute of Toxicology, Heinrich-Heine-University, 40225 Duesseldorf and
2 Institute of Occupational Physiology at the University of Dortmund, 44139 Dortmund, Germany

The tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to increase the expression of prostaglandin endoperoxide H synthase (PGHS)-2. This study focused on the regulatory mechanism of TCDD-mediated transcriptional activation of PGHS-2. Treatment of rat hepatocytes with TCDD led to a dose-dependent induction of PGHS-2 mRNA levels associated with an increased synthesis of prostaglandin E2, whereas expression of PGHS-1 was not affected. In vitro experiments with c-Src inhibitors, such as herbimycin A and geldanamycin, and in vivo studies with c-Src-deficient mice indicated that up-regulation of PGHS-2 but not the cytochrome P450 gene CYP1A1 by TCDD is mediated via a c-Src-dependent pathway. Transient transfection studies with different reporter constructs of the murine PGHS-2 promoter mutated in the xenobiotic-responsive element (XRE) or CCAAT/enhancer binding protein (C/EBP) element revealed that a C/EBP-binding site is an important regulatory cis-acting factor for trans-activation of the PGHS-2 gene by TCDD. Consistent with transfection studies, gel mobility shift assays showed that TCDD led to an enhanced DNA-binding activity of C/EBPß transcription factor. The experimental data presented in this article reveal a XRE-independent and c-Src-mediated activation of the PGHS-2 gene by TCDD through the C/EBP response element located in its promoter region.


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