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PMID:15310238

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Citation

Bodwell, JE, Kingsley, LA and Hamilton, JW (2004) Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression: complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding domain. Chem. Res. Toxicol. 17:1064-76

Abstract

Arsenic (As) contamination of drinking water is considered a principal environmental health threat throughout the world. Chronic intake is associated with an increased risk of cancer, diabetes, and cardiovascular disease, and recent studies suggest increased health risks at levels as low as 5-10 ppb. We report here that 0.05-1 microM (6-120 ppb) As showed stimulatory effects on glucocorticoid receptor (GR)-mediated gene activation in rat EDR3 hepatoma cells of both the endogenous tyrosine aminotransferase (TAT) gene and the reporter genes containing TAT glucocorticoid response elements. At slightly higher concentrations (1-3 microM), the effects of As became inhibitory. Thus, over this narrow concentration range, the effects of As changed from a 2- to 4-fold stimulation to a greater than 2-fold suppression in activity. Interestingly, the inhibitory effect of GR on both AP1- and NF-kappa B-mediated gene activation was not affected by As. The magnitude of GR stimulation and inhibition by As was highly dependent on the cellular level of hormone-activated GR. Mutational deletion studies indicated that the central DNA binding domain (DBD) of GR is the minimal region required for the As effect and does not require free sulfhydryls. Point mutations located within the DBD that have known structural consequences significantly altered the GR response to As. In particular, point mutations in the DBD that confer a DNA-bound GR confirmation abolished the low dose As stimulatory effect but enhanced the inhibitory response, further indicating that the DBD is important for mediating these As effects.

Links

PubMed Online version:10.1021/tx0499113

Keywords

Animals; Arsenic/chemistry; Arsenic/pharmacology; Base Sequence; Cell Line, Tumor; Cysteine/chemistry; DNA-Binding Proteins/chemistry; Dexamethasone/pharmacology; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation; Humans; Molecular Sequence Data; Mutation; Promoter Regions, Genetic; Protein Conformation; Rats; Receptors, Glucocorticoid/chemistry; Receptors, Glucocorticoid/metabolism; Transcription, Genetic/drug effects; Transcriptional Activation; Tyrosine Transaminase/genetics; Water Pollutants, Chemical/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:GCR

involved_in

GO:0065003: protein-containing complex assembly

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

RAT:GCR

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:GCR

involved_in

GO:0046685: response to arsenic-containing substance

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:GCR

enables

GO:0008270: zinc ion binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

RAT:GCR

enables

GO:0046983: protein dimerization activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete


See also

References

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