Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1-p300 complex
Chromium(VI) inhibits mouse metallothionein-I gene transcription by preventing the zinc-dependent formation of an MTF-1-p300 complex
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DOI：
10.1042/bj20081025
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发表时间：
2008-11-01
影响因子：
4.1
通讯作者：
Andrews, Glen K.
中科院分区：
文献类型：
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作者：
Kimura, Tomoki;Li, Yong;Andrews, Glen K.
小鼠MT-I（metallothionein-1）转录受MTF-1（metal-response-element-binding transcriptionfactor-1）调节，MTF-1响应于锌被募集到启动子。铬（VI）[铬（VI）]预处理阻断锌激活的内源性MT-I基因，并减弱锌激活的MT-I启动子驱动的荧光素酶报告基因在瞬时转染试验。染色质免疫沉淀试验表明，铬（VI）只适度减少招聘的MTF-1的MT-I启动子响应锌，但大大减少了招聘的RNA聚合酶II。这些结果表明，铬（VI）抑制MTF-1的能力，以反式激活该基因的锌。最近已经显示锌诱导含有MTF-1和组蛋白乙酰转移酶p300的共激活剂复合物的形成，所述共激活剂复合物在MT-I转录的激活中起重要作用。在本研究中，共免疫沉淀试验表明，铬（VI）预处理块锌诱导形成的这种共激活剂复合物。因此，Cr（VI）通过干扰MTF-1形成含有p300的共激活复合物的能力并将RNA聚合酶II募集到启动子上来抑制小鼠MT-I基因对锌的反应。
Mouse MT-I (metallothionein-1) 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 enclogenous 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 ail 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.