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Archives of Toxicology

, Volume 89, Issue 11, pp 2027–2038 | Cite as

Novel role of hnRNP-A2/B1 in modulating aryl hydrocarbon receptor ligand sensitivity

  • See-Wun Cho
  • Ken-ichi Suzuki
  • Yoshiaki Miura
  • Tatsuhiko Miyazaki
  • Masato Nose
  • Hisato Iwata
  • Eun-Young KimEmail author
Molecular Toxicology

Abstract

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.

Keywords

AHR Sensitivity FICZ TCDD C3H/lpr MRL/lpr hnRNP-A2/B1 

Notes

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology to E.-Y. Kim (2013R1A1A2A10010043 and 2012K2A2A4021504). This study was also supported by Grants-in-Aid for Scientific Research (S) (Nos. 21221004 and 26220103) and Challenging Exploratory Research (No. 25660228) to H.I. from Japan Society for the Promotion of Science.

Supplementary material

204_2014_1352_MOESM1_ESM.docx (1.3 mb)
Supplementary material 1 (DOCX 1337 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • See-Wun Cho
    • 1
    • 2
  • Ken-ichi Suzuki
    • 3
  • Yoshiaki Miura
    • 4
  • Tatsuhiko Miyazaki
    • 5
  • Masato Nose
    • 5
    • 6
  • Hisato Iwata
    • 4
  • Eun-Young Kim
    • 1
    • 2
    Email author
  1. 1.Department of Life and Nanopharmaceutical ScienceKyung Hee UniversitySeoulKorea
  2. 2.Department of BiologyKyung Hee UniversitySeoulKorea
  3. 3.Graduate School of ScienceHiroshima UniversityHiroshimaJapan
  4. 4.Center for Marine Environmental Studies (CMES)Ehime UniversityMatsuyamaJapan
  5. 5.Department of PathogenomicsEhime University Graduate School of MedicineToonJapan
  6. 6.Department of HistopathologyTohoku University Graduate School of MedicineSendaiJapan

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