Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1-p300 complex.
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.
Kimura
Tomoki
T
Department of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan. tomoki@pharm.setsunan.ac.jp
Li
Yong
Y
Okumura
Fumika
F
Itoh
Norio
N
Nakanishi
Tsuyoshi
T
Sone
Tomomichi
T
Isobe
Masakazu
M
Andrews
Glen K
GK
D000818:Animals; D002857:Chromium / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015032:Zinc / Q000378:metabolism*; D000097809:Transcription Factor MTF-1
D002857:Chromium; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein; D008668:Metallothionein; D012319:RNA Polymerase II; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C074702:chromium hexavalent ion; C494361:Ep300 protein, mouse