Journal Article

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-Bahay, Regine Kahl, Gisela H. Degen and Josef Abel

in Carcinogenesis

Volume 21, issue 12, pages 2267-2274
Published in print December 2000 | ISSN: 0143-3334
Published online December 2000 | e-ISSN: 1460-2180 | DOI:
Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway

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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/EBPβ 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.

Keywords: AhR, aromatic hydrocarbon receptor; ATF/CRE, activating transcription factor/cyclic AMP response element; C/EBP, CCAAT/enhancer binding protein; CYP1A1, mammalian cytochrome P450; PGE2, prostaglandin E2; PGHS, prostaglandin endoperoxide H synthase; c-Src, tyrosine kinase pp60src; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin); XRE, xenobiotic-responsive element

Journal Article.  7258 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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