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Glucocorticoid Receptor‐Mediated Transcriptional Regulation of N‐acetyltransferase 1 Gene through Distal Promoter
Author(s) -
Bonamassa Barbara,
Ma Jongjie,
Liu Dexi
Publication year - 2012
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.26.1_supplement.lb570
Subject(s) - transfection , glucocorticoid receptor , reporter gene , microbiology and biotechnology , gene expression , biology , nuclear receptor , gene , glucocorticoid , cell culture , regulation of gene expression , pregnane x receptor , chloramphenicol acetyltransferase , promoter , transcription factor , genetics , endocrinology
Human arylamine N‐acetyltransferase 1, HUMAN(NAT1) plays important roles in drug and carcinogen biotransformation and cancer development. Its gene expression has been shown to be regulated by environmental factors. The purpose of the current study is to determine the involvement of nuclear receptors in its transcriptional regulation. We show that among the nuclear receptors, the glucocorticoid receptor (GR) plays a dominant role on the distal promoter (P3). The involvement of the GR was demonstrated by dexamethasone treatment, reporter assay using plasmid‐containing 3kbp of 5′ end region of P3, and treatment of anti‐glucocorticoid RU486 in primary human hepatocytes and transfected HepG2 cells. In addition, translation inhibition didn't affect dexamethasone‐induced gene expression through P3, suggesting that dexamethasone effect is directly mediated by GR activation. Furthermore, deletion analysis revealed the presence of multiple responsive elements. Transfection assays in mice using hydrodynamics‐based procedure and reporter gene assay in a mouse cell line revealed that GR‐induced NAT gene expression is species dependent. Dexamethasone treatment of transfected mice and mouse cell line decreased mouse NAT2 gene expression, HUMAN(NAT1) homologue. These results suggest that glucocorticoids serve as a modulator for (HUMAN)NAT1 gene expression via the P3‐containing 5′‐flanking region. (NIH grant RO1EB007357 and RO1HL098295)