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Transrepression of Estrogen Receptor ß Signaling by Nuclear Factor-B in Ovarian Granulosa Cells

Prince Henry’s Institute of Medical Research and the Department of Medicine (S.C., P.J.F.), Monash University, Clayton, Victoria 3168, Australia; and Department of Medicine and Bioregulatory Science (Y.N., T.Y., H.N., P.J.F.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan

Address all correspondence and requests for reprints to: Professor Peter J. Fuller, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: peter.fuller{at}phimr.monash.edu.au.

Estrogen receptor (ER) ß is the predominant ER in granulosa cells of the ovary. ERß is expressed at high levels in granulosa cell tumors (GCT) and in the human GCT-derived cell lines, COV434 and KGN. To gain insight into ERß function in granulosa cells and in GCT, we have used the COV434 and KGN cell lines. Although the cells bind estradiol (E₂), transcriptional activation of a transfected estrogen-responsive reporter vector construct (ERE₂-luc) by E₂ was not observed. Transactivation was also not observed with cotransfected ER or ß. This transcriptional resistance is specific to steroid receptor transactivation; reporter plasmids that are activated by the transcription factors activator protein 1 (AP-1) and nuclear factor B (NF-B) demonstrate both constitutive and inducible transactivation. AP-1 and NF-B are known to cause transrepression of both ER- and glucocorticoid receptor-mediated transcription. We therefore examined the possibility that activation of these pathways was responsible for the lack of a response to estrogen by using inhibitors of AP-1 or NF-B. The AP-1 inhibitors alone had no effect, whereas inhibition of NF-B signaling allowed a 3- to 4-fold E₂-mediated induction of ERE₂-luc. This response was both ligand and ER dependent. Repression of ERß signaling by NF-B has not previously been reported. Recent evidence suggests that ERß may function to promote differentiation. The inhibition of ERß in combination with the antiapoptotic properties of NF-B may therefore contribute to pathogenesis of GCT.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol

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