title: Chromium (VI) inhibits mouse metallothionein-I gene transcription by modifying the transcription potential of the co-activator p300.
abstract: The production of the heavy metal-binding proteins, the metallothioneins (MTs), is induced by heavy metals such as Zn, Cd, and Hg. MTs maintain Zn homeostasis and attenuate heavy metal-induced cytotoxicity by sequestering these metals and lowering their intracellular concentrations. Previously, we had reported that Zn induced the formation of a co-activator complex containing metal response element-binding transcription factor-1 (MTF-1) and the histone acetyltransferase (HAT), p300, which plays an essential role in the activation of MT-1 transcription. In addition, we had shown that Cr(VI) inhibits Zn-induced MT-1 transcription by preventing the Zn-dependent formation of the MTF-1-p300 complex. In the current study, we have shown that the inhibition by Cr(VI) was partially overcome by the overexpression of p300 or MTF-1 in an MT-I promoter-driven luciferase reporter assay system and have used real-time RT-PCR to determine MT-I mRNA levels. It has been reported that Cr(VI) inhibits CYP1A1 transcription by crosslinking histone deacetylase (HDAC) to the promoter. The crosslink inhibits the recruitment of p300 to the MT-1 promoter and blocks HAT-dependent transactivation by p300. However, our results demonstrate that trichostatin A, an HDAC inhibitor, could not block the inhibitory effects of Cr(VI) on MT-1 transcription and that there were no significant differences in the in vitro inhibitory effects of Cr(VI), Cr(III), and Zn on p300 HAT activity. This suggests that the inhibitory effects of Cr(VI) on MT-I transcription may be due to its effects on the HAT-independent transactivation ability rather than the HAT-dependent, HDAC release-related transactivation ability of p300.
authors.affiliation: Department of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, Japan. tomoki@pharm.setsunan.ac.jp
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kimura
authors.forename: Fumika
authors.initials: F
authors.lastname: Okumura
authors.forename: Akira
authors.initials: A
authors.lastname: Onodera
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Norio
authors.initials: N
authors.lastname: Itoh
authors.forename: Masakazu
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002857:Chromium / Q000633:toxicity*; D003432:Cross-Linking Reagents / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D000097809:Transcription Factor MTF-1
chemical_list: D002857:Chromium; D003432:Cross-Linking Reagents; D019363:Cytochrome P-450 CYP1A1; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein; D006655:Histone Deacetylases; D008668:Metallothionein; D012333:RNA, Messenger; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C525355:metallothionein-1, mouse; C074702:chromium hexavalent ion; C494361:Ep300 protein, mouse