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Kimura, T, Li, Y, Okumura, F, Itoh, N, Nakanishi, T, Sone, T, Isobe, M and Andrews, GK (2008) Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1-p300 complex. Biochem. J. 415:477-82
Mouse MT-I (metallothionein-I) transcription is regulated by MTF-1 (metal-response-element-binding transcription factor-1) which is recruited to the promoter in response to zinc. Cr(VI) [chromium(VI)] pretreatment blocks zinc-activation of the endogenous MT-I gene and attenuates zinc-activation of MT-I-promoter-driven luciferase reporter genes in transient transfection assays. Chromatin immunoprecipitation assays revealed that Cr(VI) only modestly reduces recruitment of MTF-1 to the MT-I promoter in response to zinc, but drastically reduces the recruitment of RNA polymerase II. These results suggest that Cr(VI) inhibits the ability of MTF-1 to transactivate this gene in response to zinc. Zinc has recently been shown to induce the formation of a co-activator complex containing MTF-1 and the histone acetyltransferase p300 which plays an essential role in the activation of MT-I transcription. In the present study, co-immunoprecipitation assays demonstrated that Cr(VI) pretreatment blocks the zinc-induced formation of this co-activator complex. Thus Cr(VI) inhibits mouse MT-I gene expression in response to zinc by interfering with the ability of MTF-1 to form a co-activator complex containing p300 and recruiting RNA polymerase II to the promoter.
Animals; Chromium/pharmacology; DNA-Binding Proteins/antagonists & inhibitors; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; E1A-Associated p300 Protein/antagonists & inhibitors; E1A-Associated p300 Protein/genetics; E1A-Associated p300 Protein/metabolism; Metallothionein/genetics; Metallothionein/metabolism; Mice; Promoter Regions, Genetic; RNA Polymerase II/genetics; RNA Polymerase II/metabolism; Response Elements; Transcription Factors/antagonists & inhibitors; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Transfection; Zinc/metabolism