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首页> 外文期刊>Archives of Toxicology >Novel role of hnRNP-A2/B1 in modulating aryl hydrocarbon receptor ligand sensitivity
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Novel role of hnRNP-A2/B1 in modulating aryl hydrocarbon receptor ligand sensitivity

机译：hnRNP-A2 / B1在调节芳烃受体配体敏感性中的新作用

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The aryl hydrocarbon receptor (AHR) is responsible for susceptibility to its ligand-dependent responses. However, the effect of non-AHR factors is less clear. To explore the non-AHR factors, we used two mouse strains with different AHR genetic variants, namely C3H/lpr and MRL/lpr strains with Ala and Val as the 375th amino acid residue, respectively. To assess the contribution of AHR alone, COS-7 cells transiently expressing AHR from each strain were treated with 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and xenobiotic-responsive element (XRE)-driven reporter gene activities were measured. FICZ-EC50 values for the C3H/lpr and MRL/lpr AHR-mediated transactivation were 0.023 and 0.046 nM, respectively, indicating a similar susceptibility in both AHR genotypes. In contrast, C3H/lpr AHR was fourfold more sensitive to TCDD than MRL/lpr AHR. By a pull-down assay using a XRE-containing PCR product as bait and the hepatic nuclear extracts of both FICZ-treated mouse strains, we identified two interacting proteins as heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP-A2) and its splicing variant (hnRNP-A2b). Immunoprecipitation assays demonstrated the AHR interaction with hnRNP-A2/B1. When hnRNP-A2 was co-expressed with the MRL/lpr or C3H/lpr AHR in COS-7, FICZ treatment decreased EC50 to about threefold in both AHR genotypes, compared with EC50 in AHR alone. Similarly, hnRNP-A2b co-expression also lowered the FICZ-EC50 values. In TCDD-treated COS-7, responses depended on the AHR genotype; while no change in TCDD-EC50 was observed for C3H/lpr AHR when hnRNP-A2 was co-expressed, the value was reduced to nearly tenfold for MRL/lpr AHR. Co-transfection with hnRNP-A2b attenuated the AHR sensitivity to TCDD. In conclusion, the hnRNP-A2/B1 interacting with AHR may be a modulator of the AHR ligand sensitivity.
机译：芳烃受体（AHR）对其配体依赖性反应易感。但是，非AHR因素的影响尚不清楚。为了探索非AHR因子，我们使用了两种具有不同AHR遗传变异的小鼠品系，即分别以Ala和Val为第375个氨基酸残基的C3H / lpr和MRL / lpr品系。为了评估单独的AHR的贡献，分别用6-甲酰基吲哚并[3,2-b]咔唑（FICZ）和2,3,7,8-四氯二苯并-p-二恶英（ TCDD）和异种反应元件（XRE）驱动的报告基因活性。 C3H / lpr和MRL / lpr AHR介导的反式激活的FICZ-EC50值分别为0.023和0.046 nM，表明两种AHR基因型的敏感性相似。相反，C3H / lpr AHR对TCDD的敏感性是MRL / lpr AHR的四倍。通过使用含XRE的PCR产物作为诱饵和两种FICZ处理的小鼠品系的肝核提取物的下拉测定法，我们鉴定了两种相互作用的蛋白，即异质核糖核蛋白A2 / B1（hnRNP-A2）及其剪接变体（ hnRNP-A2b）。免疫沉淀分析表明AHR与hnRNP-A2 / B1相互作用。当hnRNP-A2与MRL / lpr或C3H / lpr AHR在COS-7中共表达时，与单独AHR中的EC50相比，FICZ治疗在两种AHR基因型中均将EC50降低至大约三倍。同样，hnRNP-A2b共表达也降低了FICZ-EC50值。在TCDD处理的COS-7中，反应取决于AHR基因型。共表达hnRNP-A2时，对于C3H / lpr AHR，未观察到TCDD-EC50的变化，但对于MRL / lpr AHR，该值降低了近十倍。与hnRNP-A2b的共转染减弱了AHR对TCDD的敏感性。总之，与AHR相互作用的hnRNP-A2 / B1可能是AHR配体敏感性的调节剂。

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