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Int. J. Mol. Sci. 2014, 15(5), 7939-7957; doi:10.3390/ijms15057939
Article

Aryl Hydrocarbon Receptor Repressor and TiPARP (ARTD14) Use Similar, but also Distinct Mechanisms to Repress Aryl Hydrocarbon Receptor Signaling

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Received: 9 April 2014; Accepted: 23 April 2014 / Published: 6 May 2014
(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)
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Abstract: The aryl hydrocarbon receptor (AHR) regulates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The AHR repressor (AHRR) is an AHR target gene and functions as a ligand-induced repressor of AHR; however, its mechanism of inhibition is controversial. Recently, we reported that TCDD-inducible poly (ADP-ribose) polymerase (TiPARP; ARTD14) also acts as a repressor of AHR, representing a new player in the mechanism of AHR action. Here we compared the ability of AHRR- and TiPARP-mediated inhibition of AHR activity. TCDD increased AHRR mRNA levels and recruitment of AHRR to cytochrome P450 1A1 (CYP1A1) in MCF7 cells. Knockdown of TiPARP, but not AHRR, increased TCDD-induced CYP1A1 mRNA and AHR protein levels. Similarly, immortalized TiPARP−/− mouse embryonic fibroblasts (MEFs) and AHRR−/− MEFs exhibited enhanced AHR transactivation. However, unlike TiPARP−/− MEFs, AHRR−/− MEFs did not exhibit increased AHR protein levels. Overexpression of TiPARP in AHRR−/− MEFs or AHRRΔ8, the active isoform of AHRR, in TiPARP−/− MEFs reduced TCDD-induced CYP1A1 mRNA levels, suggesting that they independently repress AHR. GFP-AHRRΔ8 and GFP-TiPARP expressed as small diffuse nuclear foci in MCF7 and HuH7 cells. GFP-AHRRΔ8_Δ1-49, which lacks its putative nuclear localization signal, localized to both the nucleus and the cytoplasm, while the GFP-AHRRΔ8_Δ1-100 mutant localized predominantly in large cytoplasmic foci. Neither GFP-AHRRΔ8_Δ1-49 nor GFP-AHRRΔ8_Δ1-100 repressed AHR. Taken together, AHRR and TiPARP repress AHR transactivation by similar, but also different mechanisms.
Keywords: aryl hydrocarbon receptor; AHR (Aryl hydrocarbon receptor) repressor; TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-inducible-poly (ADP-ribose) polymerase; ADP-ribosyltransferase diptheria-like toxin 14; 2,3,7,8-tetrachlorodibenzo-p-dioxin; transactivation aryl hydrocarbon receptor; AHR (Aryl hydrocarbon receptor) repressor; TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-inducible-poly (ADP-ribose) polymerase; ADP-ribosyltransferase diptheria-like toxin 14; 2,3,7,8-tetrachlorodibenzo-p-dioxin; transactivation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

MacPherson, L.; Ahmed, S.; Tamblyn, L.; Krutmann, J.; Förster, I.; Weighardt, H.; Matthews, J. Aryl Hydrocarbon Receptor Repressor and TiPARP (ARTD14) Use Similar, but also Distinct Mechanisms to Repress Aryl Hydrocarbon Receptor Signaling. Int. J. Mol. Sci. 2014, 15, 7939-7957.

AMA Style

MacPherson L, Ahmed S, Tamblyn L, Krutmann J, Förster I, Weighardt H, Matthews J. Aryl Hydrocarbon Receptor Repressor and TiPARP (ARTD14) Use Similar, but also Distinct Mechanisms to Repress Aryl Hydrocarbon Receptor Signaling. International Journal of Molecular Sciences. 2014; 15(5):7939-7957.

Chicago/Turabian Style

MacPherson, Laura; Ahmed, Shaimaa; Tamblyn, Laura; Krutmann, Jean; Förster, Irmgard; Weighardt, Heike; Matthews, Jason. 2014. "Aryl Hydrocarbon Receptor Repressor and TiPARP (ARTD14) Use Similar, but also Distinct Mechanisms to Repress Aryl Hydrocarbon Receptor Signaling." Int. J. Mol. Sci. 15, no. 5: 7939-7957.


Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert