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and ß1
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292
Address all correspondence and requests for reprints to: Carolyn M. Klinge, Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292. E-mail carolyn.klinge{at}louisville.edu
Epidemiological evidence indicates that phytoestrogens inhibit cancer
formation and growth, reduce cholesterol levels, and show benefits in
treating osteoporosis. At least some of these activities are mediated
through the interaction of phytoestrogens with estrogen receptors 
and ß (ER and ERß). Resveratrol,
trans-3,5,4'-trihydroxystilbene, is a phytoestrogen in
grapes that is present in red wine. Resveratrol was shown to bind ER in
cytosolic extracts from MCF-7 and rat uteri. However, the contribution
of ER vs. ERß in this binding is unknown. Here we
report that resveratrol binds ERß and ER with comparable affinity,
but with 7,000-fold lower affinity than estradiol (E2).
Thus, resveratrol differs from other phytoestrogens that bind ERß
with higher affinity than ER. Resveratrol acts as an estrogen
agonist and stimulates ERE-driven reporter gene activity in CHO-K1
cells expressing either ER or ERß. The estrogen agonist activity
of resveratrol depends on the ERE sequence and the type of ER.
Resveratrol-liganded ERß has higher transcriptional activity than
E2-liganded ERß at a single palindromic ERE. This
indicates that those tissues that uniquely express ERß or that
express higher levels of ERß than ER may be more sensitive to
resveratrol’s estrogen agonist activity. For the natural, imperfect
EREs from the human c-fos, pS2, and progesterone
receptor (PR) genes, resveratrol shows activity comparable to that
induced by E2. We report that resveratrol exhibits
E2 antagonist activity for ER with select EREs. In
contrast, resveratrol shows no E2 antagonist activity with
ERß. These data indicate that resveratrol differentially affects the
transcriptional activity of ER and ERß in an ERE
sequence-dependent manner.
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