Abstract
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-alpha (TNF-alpha)-induced transcriptional competence of nuclear factor-kappaB (NF-kappaB) in A549 human lung carcinoma cells. Pretreatment of A549 cells with nontoxic levels of Cr(VI) inhibited TNF-alpha-stimulated expression of the endogenous gene for interleukin-8 and of an NF-kappaB-driven luciferase gene construct, but not expression of urokinase, a gene with a more complex promoter. Chromium did not inhibit TNF-alpha-stimulated IkappaBalpha degradation or translocation of NF-kappaB-binding proteins to the nucleus. However, Cr(VI) pretreatments prevented TNF-alpha-stimulated interactions between the p65 subunit of NF-kappaB 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-kappaB transcriptional competence by inhibiting interactions with coactivators of transcription rather than DNA binding.
Highlights
IntroductionCr(VI) affects expression of various genes, including catalase, heme oxygenase, 5-aminolevulinate synthase, and urokinase plasminogen activator receptor [1,2,3]
Chromium(VI) promotes pulmonary fibrosis and is a human carcinogen
Cr(VI) Decreases TNF-␣-stimulated IL-8 mRNA Expression—IL-8 mRNA is not expressed basally in A549 cells, and previous work has demonstrated that it is not induced in response to Cr(VI) [15]
Summary
Cr(VI) affects expression of various genes, including catalase, heme oxygenase, 5-aminolevulinate synthase, and urokinase plasminogen activator receptor [1,2,3] These chromium-mediated changes in gene expression are attributed to the generation of reactive chromium and oxygen species, DNA damage, or alterations in mRNA stability. This study examined whether Cr(VI) has additional effects on gene expression at the level of transcription factor activation or transcriptional competence. Nuclear factor-B (NF-B) is a mammalian transcription activator protein involved in regulating expression of immune and inflammatory response genes. It occurs in both homo- and heterodimeric forms. In addition to DNA binding, the interaction of p65 with CREB-binding protein (CBP) is essential for NF-B-enhanced transcriptional activity [5, 6].
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