Aryl Hydrocarbon Receptor Repressor and TiPARP (ARTD14) Use Similar,but also Distinct Mechanisms to Repress Aryl Hydrocarbon Receptor Signaling |
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Authors: | Laura MacPherson Shaimaa Ahmed Laura Tamblyn Jean Krutmann Irmgard F?rster Heike Weighardt Jason Matthews |
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Affiliation: | 1.Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; E-Mails: (L.M.); (S.A.); (L.T.);2.IUF-Leibniz Research Institute for Environmental Medicine gGmbH, Auf’m Hennekamp 50, 40225 Düsseldorf, Germany; E-Mail: ;3.Immunology and Environment, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Straβe 31, 53115 Bonn, Germany; E-Mails: (I.F.); (H.W.) |
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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. |
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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 |
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