Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors.

Ema, Makoto; Ohe, Norihisa; Suzuki, Michiko; Mimura, Junsei; Sogawa, Kazuhiro; Ikawa, Shuntaro; Fujii‐Kuriyama, Yoshiaki

doi:10.1016/s0021-9258(18)46990-6

Cited by 303 publications

(73 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results indicate that endogenous TGFb might be partially implicated in inhibition of CYP1A1 and CYP1B1 expression. Of note, similar inhibitory effects by TGFb were observed both in human and mouse cells even though the human AhR not only shares limited sequence identity to mouse AhR but also shows different affinity to TCDD or other AhR ligands to mouse AhR (31)(32)(33)(34).…”

Section: Resultsmentioning

confidence: 56%

Dissociation of the AhR/ARNT complex by TGF-β/Smad signaling represses CYP1A1 gene expression and inhibits benze[a]pyrene-mediated cytotoxicity

Nakano

Sakata

Katsu

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cytochrome P450 1A1 (CYP1A1) catalyzes the metabolic activation of polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) and is transcriptionally regulated by the aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) complex upon exposure to PAHs. Accordingly, inhibition of CYP1A1 expression reduces production of carcinogens from PAHs. Although transcription of the CYP1A1 gene is known to be repressed by transforming growth factor-β (TGF-β), how TGF-β signaling is involved in the suppression of CYP1A1 gene expression has yet to be clarified. In this study, using mammalian cell lines, along with shRNA-mediated gene silencing, CRISPR/Cas9-based genome editing, and reporter gene and quantitative RT-PCR assays, we found that TGF-β signaling dissociates the B[a]P-mediated AhR/ARNT heteromeric complex. Among the examined Smads, Smad family member 3 (Smad3) strongly interacted with both AhR and ARNT via its MH2 domain. Moreover, hypoxia-inducible factor 1α (HIF-1α), which is stabilized upon TGF-β stimulation, also inhibited AhR/ARNT complex formation in the presence of B[a]P. Thus, TGF-β signaling negatively regulated the transcription of the CYP1A1 gene in at least two different ways. Of note, TGF-β abrogated DNA damage in B[a]P-exposed cells. We therefore conclude that TGF-β may protect cells against carcinogenesis because it inhibits CYP1A1-mediated metabolic activation of PAHs as part of its anti-tumorigenic activities.

show abstract

Section: Resultsmentioning

confidence: 56%

Dissociation of the AhR/ARNT complex by TGF-β/Smad signaling represses CYP1A1 gene expression and inhibits benze[a]pyrene-mediated cytotoxicity

Nakano

Sakata

Katsu

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…For example, mouse AHR binds TCDD with a tenfold higher ligand affinity than its human ortholog, owing to a single amino acid residue difference in the middle of the ligand binding pocket (valine 381 in human AHR corresponding to alanine 375 in mouse AHR) (Ramadoss and Perdew 2004). Similarly, the decreased ligand binding affinity of the murine Ahr d allele compared to Ahr b is the result of a single amino acid substitution, from V375 in AHR b to A375 in AHR d (Chang et al 1993;Ema et al 1994;Poland et al 1994).…”

Section: Ahr Evolution and Primary Structurementioning

confidence: 99%

Ac9

2018

Encyclopedia of Signaling Molecules

View full text Add to dashboard Cite

show abstract

“…o Several other studies reported the importance of this amino acid in birds and mammals (Backlund and Ingelman-Sundberg 2004;Ema et al 1994;Murray et al 2005;Pandini et al 2007;Pandini et al 2009;Poland et al 1994;Ramadoss and Perdew 2004).…”

Section: Ahr Ligand Binding Domainmentioning

confidence: 99%

“…o A 10-fold difference between two strains of mice (non-responsive DBA/2 mouse, and responsive C57BL/6 14 mouse) in CYP1A induction, lethality and teratogenicity following TCDD exposure , was attributed to a single nucleotide polymorphism at position 375 (Ema et al 1994;Poland et al 1994;Poland and Knutson 1982).…”

Section: Ahr Ligand Binding Domainmentioning

confidence: 99%

See 1 more Smart Citation

OECD Series on Adverse Outcome Pathways

View full text Add to dashboard Cite

Events Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO) Sequence Type Event ID Title Short name 1 MIE 18 Activation, AhR Activation, AhR 2 KE 944 dimerization, AHR/ARNT dimerization, AHR/ARNT 3 KE 945 reduced dimerization, ARNT/HIF1-alpha reduced dimerization, ARNT/HIF1-alpha 4 KE 948 reduced production, VEGF reduced production, VEGF 5 KE 110 Impairment, Endothelial network Impairment, Endothelial network 6 KE 317 Altered, Cardiovascular development/function Altered, Cardiovascular development/function 7 AO 947 Stressors Name Evidence Polychlorinated biphenyl High Polychlorinated dibenzodioxins High Polychlorinated dibenzofurans High

show abstract

Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors.

Cited by 303 publications

References 35 publications

Dissociation of the AhR/ARNT complex by TGF-β/Smad signaling represses CYP1A1 gene expression and inhibits benze[a]pyrene-mediated cytotoxicity

Dissociation of the AhR/ARNT complex by TGF-β/Smad signaling represses CYP1A1 gene expression and inhibits benze[a]pyrene-mediated cytotoxicity

Ac9

OECD Series on Adverse Outcome Pathways

Contact Info

Product

Resources

About