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J. Biol. Chem. 279 (23): 24007-24014

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Green Tea Polyphenol and Curcumin Inversely Regulate Human Involucrin Promoter Activity via Opposing Effects on CCAAT/Enhancer-binding Protein Function*

Sivaprakasam Balasubramanian{ddagger}§, and Richard L. Eckert{ddagger}¶||**{ddagger}{ddagger}§§

Departments of {ddagger}Physiology and Biophysics, Dermatology, ||Biochemistry, **Reproductive Biology, and {ddagger}{ddagger}Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970

Abstract: Antioxidants are important candidate agents for the prevention of disease. However, the possibility that different antioxidants may produce opposing effects in tissues has not been adequately explored. We have reported previously that (–)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol antioxidant, stimulates expression of the keratinocyte differentiation marker, involucrin (hINV), via a Ras, MEKK1, MEK3, p38{delta} signaling cascade (Balasubramanian, S., Efimova, T., and Eckert, R. L. (2002) J. Biol. Chem. 277, 1828–1836). We now show that EGCG activation of this pathway results in increased CCAAT/enhancer-binding protein (C/EBP{alpha} and C/EBP{beta}) factor level and increased complex formation at the hINV promoter C/EBP DNA binding site. This binding is associated with increased promoter activity. Mutation of the hINV promoter C/EBP binding site eliminates the regulation as does expression of GADD153, a dominant-negative C/EBP factor. In contrast, a second antioxidant, curcumin, inhibits the EGCG-dependent promoter activation. This is associated with inhibition of the EGCG-dependent increase in C/EBP factor level and C/EBP factor binding to the hINV promoter. Curcumin also inhibits the EGCG-dependent increase in endogenous hINV levels. The curcumin-dependent suppression of C/EBP factor level is inhibited by treatment with the proteasome inhibitor MG132, suggesting that the proteasome function is required for curcumin action. We conclude that curcumin and EGCG produce opposing effects on involucrin gene expression via regulation of C/EBP factor function. The observation that two antioxidants can produce opposite effects is an important consideration in the context of therapeutic antioxidant use.

Received for publication December 31, 2003. Revision received March 19, 2004.

* This work was supported by grants from the National Institutes of Health (to R. L. E.) and used the facilities of the Skin Diseases Research Center of Northeast Ohio, which is supported by National Institutes of Health Grant AR39750. 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.

§ Recipient of an O-CHA (Tea) Pioneer Academic Research Grant from the World Green Tea Association.

§§ To whom correspondence should be addressed: Dept. of Physiology/Biophysics, Case Western Reserve University School of Medicine, 2109 Adelbert Rd., Cleveland, OH 44106-4970. Tel.: 216-368-5530; Fax: 216-368-5586.

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