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Departments of Cell and Structural Biology, and Molecular and Integrative Physiology, University of Illinois (T.R.E., B.S.K.), Urbana, Illinois 61801; the Department of Biology, University of California (W.L.K.), La Jolla, California 92093; the Department of Medicine, West Virginia University Medical Center (E.J.W.), Morgantown, West Virginia 26506; and the Department of Veterans Affairs Medical Center (E.J.W.), Clarksburg, West Virginia 26301
Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, Department of Molecular and Integrative Physiology, University of Illinois, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}uiuc.edu
To better understand the actions of estrogens and antiestrogens in
estrogen target cells, we have searched for estrogen-regulated genes in
human breast cancer cells, in which the number of genes known to be
directly activated by estrogen is quite small. Using differential
display RNA methods, we have identified the human homolog of the
Na+-H+ exchanger regulatory factor (NHE-RF), an
approximately 50-kDa protein that is also an
ezrin-radixin-moesin-binding phosphoprotein, as being under rapid and
direct regulation by estrogen in estrogen receptor (ER)-containing
breast cancer cells. Stimulation by estrogen of NHE-RF RNA is rapid,
being near maximal (
6-fold) by 1 h, and is not blocked
by cycloheximide, indicating that it is a primary response. Stimulation
is selective for estrogen ligands, with no stimulation by other classes
of steroid hormones, and stimulation by estrogen is suppressed by the
antiestrogens tamoxifen and ICI 182,780. Induction is shown to require
an active ER through several approaches, including the use of
ER-negative breast cancer cells containing a stably integrated ER.
NHE-RF protein levels, monitored using antibodies specific for this
protein, increase after estrogen and reach maximal levels at 24–48 h.
Interestingly, NHE-RF is a PDZ domain-containing protein that is
enriched in polarized epithelia, where it is known to be localized in
microvilli. Among various human tissues we have examined, we found that
NHE-RF is expressed at a fairly high level in mammary tissue. NHE-RF
regulates protein kinase A inhibition of the
Na+-H+ exchanger and may serve as a scaffold
adaptor protein that contributes to the specificity of signal
transduction events. Our findings suggest that the early, known effects
of estrogen on cell cytoarchitecture (e.g. increasing
microvilli on breast cancer cells) and on some cell signaling pathways
(e.g. those involving cAMP) may involve rapid
estrogen-mediated changes in the production of NHE-RF.
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Q. Zhou, L. Clarke, R. Nie, K. Carnes, L.-W. Lai, Y.-H. H. Lien, A. Verkman, D. Lubahn, J. S. Fisher, B. S. Katzenellenbogen, et al. Estrogen action and male fertility: Roles of the sodium/hydrogen exchanger-3 and fluid reabsorption in reproductive tract function PNAS, October 31, 2001; (2001) 241245898. [Abstract] [Full Text] [PDF]
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Q. Zhou, L. Clarke, R. Nie, K. Carnes, L.-W. Lai, Y.-H. H. Lien, A. Verkman, D. Lubahn, J. S. Fisher, B. S. Katzenellenbogen, et al. From the Cover: Estrogen action and male fertility: Roles of the sodium/hydrogen exchanger-3 and fluid reabsorption in reproductive tract function PNAS, November 20, 2001; 98(24): 14132 - 14137. [Abstract] [Full Text] [PDF]
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