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J. Biol. Chem., Vol. 277, Issue 17, 14622-14628, April 26, 2002
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From the George Whipple Laboratory for Cancer Research, Departments
of Pathology, Urology, and Radiation Oncology, University of Rochester
Medical Center, Rochester, New York 14642
The human testicular orphan receptor 4 (TR4) is
a member of the nuclear receptor superfamily that shows a broad tissue
distribution with higher expression in the nervous system and male
reproductive tract. TR4 functions as a transcriptional modulator that
controls various target genes via binding to the DNA hormone response
elements. Here we report that instead of direct binding to hormone
response elements for gene regulation, TR4 can also go through direct
protein-protein interaction to repress estrogen receptor (ER)-mediated
transactivation. Electrophoretic mobility shift and glutathione
S-transferase pull-down assays clearly demonstrate
that the direct interaction between TR4 and ER will inhibit the
homodimerization of ER and interrupt/prevent ER binding to the estrogen
response element. The consequence of these events may then result in
the suppression of ER target genes, such as cyclin D1 and pS2 and
inhibition of ER-mediated cell proliferation in the MCF-7 cells stably
transfected with TR4. Together, our results showing that TR4 can
suppress ER function via protein-protein interaction not only represent
a unique cross-talk signaling pathway in the nuclear receptor
superfamily, it may also provide us with a new strategy to modulate ER
function in the breast cancer cells.
Modulation of Estrogen Receptor-mediated Transactivation by
Orphan Receptor TR4 in MCF-7 Cells*
*
This work was supported by National Institutes of Health
Grant DK47258.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 585-275-9994;
Fax: 585-756-4133; E-mail: chang@urmc.rochester.edu.
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