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J. Biol. Chem., Vol. 279, Issue 10, 8886-8894, March 5, 2004

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Dioxin Increases C/EBP Transcription by Activating cAMP/Protein Kinase A^*

Christoph F. A. Vogel, Eric Sciullo, Sujin Park, Christian Liedtke¶, Christian Trautwein¶, and Fumio Matsumura||

From the Department of Environmental Toxicology, University of California, Davis, California 95616 and the ^¶Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, 30625 Hannover, Lower Saxony 30625, Germany

The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD = dioxin) has been shown to increase the expression of C/EBP. The modulated expression of C/EBP has been suggested to be associated with toxic responses of TCDD such as wasting syndrome, diabetes, and inhibition of adipocyte differentiation. This study focused on the regulatory mechanism of TCDD-mediated transcriptional activation of C/EBP. Elevated C/EBP mRNA and protein levels in mouse embryonic fibroblasts (C3H10T) and in mouse hepatoma cells (Hepa1c1c7) were correlated with increased binding affinity of the C/EBP protein. Transfection studies with different deletion constructs of the CCAAT/enhancer-binding protein promoter indicated that a small region located 60–120 bp upstream of the start site of transcription is required for activation of the C/EBP gene by TCDD in both cell lines tested. Further analysis using mutation constructs of the C/EBP promoter demonstrated that activation of the C/EBP promoter is mediated through incomplete cAMP-response element-binding protein (CREB) sites located close to the TATA box of the C/EBP gene. The protein kinase A (PKA) inhibitor H89 completely blocks the TCDD-dependent effect on C/EBP promoter activity, indicating that TCDD activates CREB binding via a cAMP/PKA pathway, which is supported by the increased cAMP level and PKA activity observed after TCDD treatment. Gel shift analyses demonstrated that CREB itself binds to the putative CREB motif that mediates the TCDD-dependent effect on C/EBP gene transcription. Cotransfection experiments with CREB and PKA expression plasmids further supported our conclusions that the TCDD-dependent effect on C/EBP transcription is mediated via PKA-dependent CREB activation.

Received for publication, September 12, 2003 , and in revised form, December 10, 2003.

^* This work was supported in part by NIEHS Research Grants RO-ESO5233 and PO-1-ES5707 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Fellowship VO 760/1-1 from the Deutsche Forschungsgemeinschaft.

^|| To whom correspondence should be addressed: Dept. of Environmental Toxicology, University of California, Davis, One Shields Ave., Davis, CA 95616. Tel.: 530-752-4251; Fax: 530-752-3394; E-mail: fmatsumura{at}ucdavis.edu.

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