Green tea polyphenol and curcumin inversely regulate human involucrin promoter activity via opposing effects on CCAAT/enhancer-binding protein function.
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, p38delta 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/EBPalpha and C/EBPbeta) 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.
Balasubramanian
Sivaprakasam
S
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, USA.
Eckert
Richard L
RL
D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002454:Cell Differentiation; D003474:Curcumin / Q000378:metabolism / Q000494:pharmacology*; D003546:Cysteine Endopeptidases; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D048371:MAP Kinase Kinase 3; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D048292:Mitogen-Activated Protein Kinase 13; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D013662:Tea; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism
D000975:Antioxidants; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D005419:Flavonoids; D009097:Multienzyme Complexes; D010636:Phenols; D059808:Polyphenols; D011498:Protein Precursors; D013662:Tea; D014157:Transcription Factors; D051742:Transcription Factor CHOP; C032253:involucrin; D002392:Catechin; D004247:DNA; C045651:epigallocatechin gallate; D048292:Mitogen-Activated Protein Kinase 13; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin