National Library of Medicine MEDLINE Database
TITL: Arsenic alters the function of the glucocorticoid receptor as a transcription factor.
AUTH: Kaltreider RC; Davis AM; Lariviere JP; Hamilton JW
ORGA: Department of Pharmacology and Toxicology, Dartmouth Medical School,
Hanover, NH 03755-3835, USA.
PUB TYPE: Journal Article.
CITE: Environmental Health Perspectives 2001 Mar; 109 (3): 245-51
LANG: ENG; English
ABST: Chronic human exposure to nonovertly toxic doses of arsenic is associated
with an increased risk of cancer. Although its carcinogenic mechanism is still
unknown, arsenic does not directly cause DNA damage or mutations and is
therefore thought to act principally as a co-mutagen, co-carcinogen, and/or
tumor promoter. Previous studies in our laboratory demonstrated that effects of
low-dose arsenic (III) (arsenite) on expression of the hormone-regulated
phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the
glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined
specifically the effects of arsenite on the biochemical function of GR in
hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite
treatments (0.3-3.3 microM) significantly decreased dexamethasone-induced
expression of transiently transfected luciferase constructs containing either an
intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem
glucocorticoid response elements (GRE). Western blotting and confocal microscopy
of a green fluorescent protein-tagged-GR fusion protein demonstrated that
arsenite pretreatment did not block the normal dexamethasone-induced nuclear
translocation of GR. These data indicate that nontoxic doses of arsenite can
interact directly with GR complexes and selectively inhibit GR-mediated
transcription, which is associated with altered nuclear function rather than a
decrease in hormone-induced GR activation or nuclear translocation.
MJTR: Arsenites, pharmacology. Carcinogens, pharmacology. Receptors,
Glucocorticoid, drug effects. Transcription Factors, drug effects.
MNTR: Animal. Arsenic Poisoning, metabolism. Blotting, Western. Carcinoma,
Hepatocellular, metabolism. Precipitin Tests. Rats. Support, U.S. Gov’t,
P.H.S.. Tumor Cells, Cultured.
RNUM: 0 (Arsenites); 0 (Carcinogens); 0 (Receptors, Glucocorticoid); 0
(Transcription Factors); 15502-74-6 (arsenite)
GEOT: United States
IDEN: ISSN: 0091-6765. JOURNAL-CODE: EI0; 0330411. ENTRY-DATE: 20010502.
NIH-GRANT-NUMBER: CA23108/CA/NCI. ES07373/ES/NIEHS. SPECIAL-LIST: IM.
JOURNAL-SUBSET: IM.
ACCE: 21231571
PMID: 11333185
