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J Biol Chem, Vol. 274, Issue 51, 36207-36212, December 17, 1999

Chromium(VI) Inhibits the Transcriptional Activity of Nuclear Factor-B by Decreasing the Interaction of p65 with cAMP-responsive Element-binding Protein-binding Protein^*

Jennifer A. Shumilla, Ryan J. Broderick^§, Yongping Wang^§¶, and Aaron Barchowsky^§

From the  Department of Chemistry, Dartmouth College and the ^§ Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835

Chromium(VI) regulation of gene expression has been attributed to the generation of reactive chromium and oxygen species, DNA damage, and alterations in mRNA stability. However, the effects of Cr(VI) on signal transduction leading to gene expression are not resolved. Therefore, this study investigated the effects of Cr(VI) on basal and tumor necrosis factor- (TNF-)-induced transcriptional competence of nuclear factor-B (NF-B) in A549 human lung carcinoma cells. Pretreatment of A549 cells with nontoxic levels of Cr(VI) inhibited TNF--stimulated expression of the endogenous gene for interleukin-8 and of an NF-B-driven luciferase gene construct, but not expression of urokinase, a gene with a more complex promoter. Chromium did not inhibit TNF--stimulated IB degradation or translocation of NF-B-binding proteins to the nucleus. However, Cr(VI) pretreatments prevented TNF--stimulated interactions between the p65 subunit of NF-B and the transcriptional cofactor cAMP-responsive element-binding protein-binding protein (CBP). This inhibition was not the result of an effect of chromium on the protein kinase A catalytic activity required for p65/CBP interactions. In contrast, Cr(VI) caused concentration-dependent increases in c-Jun/CBP interactions. These data indicate that nontoxic levels of hexavalent chromium selectively inhibit NF-B transcriptional competence by inhibiting interactions with coactivators of transcription rather than DNA binding.

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^* This work was supported by Environmental Protection Agency Superfund Basic Research Program Project Grant ES07373 and NHLBI, National Institutes of Health Grant HL52738.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ A Howard Hughes Medical Institute Predoctoral Fellow.

To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Dartmouth Medical School, 7650 Remsen, Hanover, NH 03755-3835. Tel.: 603-650-1673; Fax: 603-650-1129; E-mail: barchowsky@dartmouth.edu.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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