The aryl hydrocarbon receptor (AhR) mediates the biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Whether the AhR can mediate enhanced transcriptional activity in the absence of ligand binding has not been established. Hepatocytes from AhR-null (AhR-KO) and wild-type (AhR-WT) neonatal mice were immortalized with Simian virus 40. Two point mutants of the AhR, A375I and A375F, were generated to test the hypothesis that the AhR requires ligand binding to exhibit signiWcant transcriptional activity, both mutants fail to bind ligand or exhibit enhanced activity in cells exposed to AhR ligands. Upon transient, co-expression of ARNT with AhR-A375I or AhR-A375F in AhR-KO cells, these mutants exhibited signiWcant ligand-independent transcriptional activity. However, in CV-1 cells, which others have previously shown to contain relatively high levels of AhR ligand(s), these AhR mutants exhibit essentially no constitutive activity. These results indicate that while the AhR can potentially exhibit activity in the absence of ligand binding, the high constitutive receptor activity observed in many cell lines appears to be due to the presence of endogenous AhR ligands.

Murray, I., Reen, R., Leathery, N., Ramadoss, P., Bonati, L., Gonzalez, F., et al. (2005). Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 442(1), 59-71 [10.1016/j.abb.2005.07.014].

Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity

BONATI, LAURA;
2005

Abstract

The aryl hydrocarbon receptor (AhR) mediates the biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Whether the AhR can mediate enhanced transcriptional activity in the absence of ligand binding has not been established. Hepatocytes from AhR-null (AhR-KO) and wild-type (AhR-WT) neonatal mice were immortalized with Simian virus 40. Two point mutants of the AhR, A375I and A375F, were generated to test the hypothesis that the AhR requires ligand binding to exhibit signiWcant transcriptional activity, both mutants fail to bind ligand or exhibit enhanced activity in cells exposed to AhR ligands. Upon transient, co-expression of ARNT with AhR-A375I or AhR-A375F in AhR-KO cells, these mutants exhibited signiWcant ligand-independent transcriptional activity. However, in CV-1 cells, which others have previously shown to contain relatively high levels of AhR ligand(s), these AhR mutants exhibit essentially no constitutive activity. These results indicate that while the AhR can potentially exhibit activity in the absence of ligand binding, the high constitutive receptor activity observed in many cell lines appears to be due to the presence of endogenous AhR ligands.
Articolo in rivista - Articolo scientifico
Ah receptor; ARNT; TCDD; Dioxin; Modeling; AhR; PhotoaYnity ligand; bHLH-PAS; IodoXavone; Simian virus 40; Immortalization
English
11-ago-2005
442
1
59
71
none
Murray, I., Reen, R., Leathery, N., Ramadoss, P., Bonati, L., Gonzalez, F., et al. (2005). Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 442(1), 59-71 [10.1016/j.abb.2005.07.014].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/3245
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