Nucleic Acids Research, Vol 26, Issue 22 5182-5189, Copyright © 1998 by Oxford University Press
Q Li, N Hu, MA Daggett, WA Chu, D Bittel, JA Johnson and GK Andrews
The roles of the bHLH-Zip protein, upstream stimulatory factor (USF), in
mouse metallothionein-I (MT-I) gene expression were examined. The promoter
contains a putative USF binding site which overlaps an antioxidant response
element (ARE) located at -101 bp relative to the transcription start point.
The USF/ARE composite element increases basal expression of the mouse MT-I
gene, and partly mediates response to oxidative stress. However, other
functions of this composite element and the in vivo roles for USF in MT-I
promoter functions have not been examined. We report studies which indicate
that USF participates via the USF/ARE element in cadmium responsiveness of
the mouse MT-I promoter. During the course of these studies a second,
higher affinity USF binding site at -223 bp was identified. Stable and
transient transfection assays in mouse hepatoma cells, using the USF/ARE in
the context of a minimal promoter and site-directed and truncation mutants
of the MT-I promoter, revealed that the USF and the ARE sites contribute to
cadmium (2-30 microM) but not zinc responsiveness, and to basal promoter
activity. Overexpression of dominant-negative (dn)USF in co-transfection
assays significantly attenuated cadmium induction of the USF/ARE in the
context of a minimal promoter, and attenuated cadmium, but not zinc,
induction of the intact MT-I promoter. A consensus E-box (CACATG) at -223
bp in the MT-I promoter was also found to bind USF in vitro , and to be
constitutively footprinted in vivo . The interaction of USF with E-box1 was
apparently 10-fold stronger than that with the USF/ARE. However, in
contrast, E-box1 was not a strong basal promoter element nor was it metal
ions responsive in mouse Hepa cells. In conclusion, these studies
demonstrate a role for USF in cadmium-specific induction of the mouse MT-I
gene, but bring into question an obligate role for USF in regulating basal
activity of this gene. The data further suggest that USF interacts with
ARE-binding proteins to influence MT-I gene expression.
ARTICLES
Participation of upstream stimulator factor (USF) in cadmium-induction of the mouse metallothionein-I gene
Department Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160- 7421, USA.
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