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Glucocorticoids enhance aryl hydrocarbon receptor expression and function in mouse hepatoma cells
Author(s) -
Riddick David S,
Bielefeld Kirsten A,
Lee Chunja
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a196
Subject(s) - aryl hydrocarbon receptor , glucocorticoid receptor , medicine , endocrinology , aryl hydrocarbon receptor nuclear translocator , antiglucocorticoid , pregnane x receptor , receptor , transfection , glucocorticoid , transcription factor , luciferase , biology , chemistry , response element , endocrine system , nuclear receptor , gene expression , cell culture , hormone , promoter , biochemistry , gene , genetics
The aryl hydrocarbon receptor (AHR) is a ligand‐activated transcription factor that mediates most biological responses to 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD). Although the AHR's role in control of drug metabolism and endocrine disruption are partly understood, we know little about the regulation of the AHR itself by endocrine factors. Our work with hypophysectomized rats suggested that hepatic AHR protein level is positively regulated by pituitary‐dependent factors. One current hypothesis is that adrenal glucocorticoids elevate AHR expression and enhance responsiveness to AHR agonists. Dexamethasone (DEX) at concentrations that activate the glucocorticoid receptor (GR) increased AHR mRNA, protein and TCDD‐binding by approximately 50% in Hepa‐1 mouse hepatoma cells. This response was blocked by the GR antagonist RU486, suggesting GR involvement. This small magnitude increase in AHR levels was functionally significant; pre‐treatment of Hepa‐1 cells with DEX caused a 75% increase in the maximum induction of an AHR‐activated luciferase reporter by TCDD. A new luciferase reporter under control of the proximal 2.5‐kb of the mouse AHR 5′‐flank was induced approximately 2‐fold by DEX but only with co‐transfection of a mouse GR expression plasmid. The molecular mechanisms and in vivo relevance of this pathway for endocrine control of AHR expression and function are being explored. [Support: CIHR]