Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor
Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor
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DOI：
10.1016/j.bbrc.2004.07.153
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发表时间：
2004-09-17
影响因子：
3.1
通讯作者：
Lacarelle, B
中科院分区：
文献类型：
--
作者：
Fallone, F;Villard, PH;Lacarelle, B
CYP 1A 1亚型主要受转录因子AhR调节，较小程度上受核受体RAR调节。与3 MC（一种AhR配体）和RA（一种RAR配体）（分别为强和弱CYP 1A 1诱导剂）共暴露的影响知之甚少。我们在Caco-2细胞中发现，加入RA可显著降低3 MC诱导的CYP 1A 1表达，mRNA水平降低约55%，启动子和酶活性降低约30%。我们进一步表明，RA降低AhR蛋白水平。此外，AhR和RAR-辅阻遏物SMRT之间的物理相互作用已经在体外进行了描述。使用辅阻遏物抑制剂TSA，转染细胞与SMRT cDNA，和免疫共沉淀实验，我们证明，RA除了抑制AhR功能，通过显着的AhR/SMRT物理相互作用。这种相互作用解释了3 MC诱导的CYP 1A 1表达降低。这种新的机制涉及类维生素A抑制AhR诱导的CYP 1A 1表达，从而更好地了解CYP 1A 1的调控。(C)2004年爱思唯尔公司All rights reserved.
CYP1A1 isoform is mainly regulated by the transcription factor AhR and to a lesser extent by the nuclear receptor RAR. The effect of a coexposure with 3MC, a AhR ligand, and RA, a RAR ligand, which are, respectively, strong and weak CYP1A1 inducers, is poorly known. We showed in Caco-2 cells that addition of RA significantly decreased 3MC-induced CYP1A1 expression by -55% for mRNA level and -30% for promoter and enzymatic activities. We further showed that RA decreased AhR protein level. Moreover, a physical interaction between AhR and the RAR-corepressor SMRT has been described in vitro. Using the corepressor inhibitor TSA, transfected-cells with SMRT cDNA, and coimmunoprecipitation experiments, we demonstrated that RA addition repressed AhR function through a marked AhR/SMRT physical interaction. This interaction explains the decrease of 3MC-induced CYP1A1 expression. This new mechanism involving the repression of AhR-induced CYP1A1 expression by retinoids allows better knowledge of the CYP1A1 regulation. (C) 2004 Elsevier Inc. All rights reserved.