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Control of Estradiol-Directed Gene Transactivation by an Intracellular Estrogen-Binding Protein and an Estrogen Response Element-Binding Protein

Division of Endocrinology, Metabolism, and Lipids (H.C.), Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322; Division of Endocrinology, Diabetes, and Metabolism (M.H.), Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90048; and University of California, Los Angeles, Orthopaedic Hospital Department of Orthopaedic Surgery (J.S.A.), Los Angeles, California 90095

Address all correspondence and requests for reprints to: John Adams, M.D., UCLA-Orthopaedic Hospital Department of Orthopaedic Surgery, 615 Charles E. Young Drive South, Room 410, Los Angeles, California 90095. E-mail: jsadams{at}mednet.ucla.edu.

New World primates exhibit a form of resistance to estrogens that is associated with overexpression of an estrogen response element (ERE)-binding protein (ERE-BP) and an intracellular estradiol (E₂)-binding protein (IEBP). Both proteins suppress E₂-mediated transcription when overexpressed in estrogen receptor- (ER)-positive cells. Although ERE-BP acts as a competitor for ERE occupancy by liganded ER, the function of IEBP and its human homolog, heat-shock protein 27 (hsp27), is less clear. In data presented here, we have used E₂-responsive human MCF-7 breast cancer cells to show that IEBP/hsp27 can regulate estrogen signaling as a cytosolic decoy for E₂ and as a protein chaperone for ER. Furthermore, co-immunoprecipitation, colocalization, yeast two-hybrid, and glutathione S-transferase pull-down analyses indicate that IEBP/hsp27 also interacts with ERE-BP to form a dynamic complex that appears to cycle between the cytoplasm and nucleus during normal estrogen signaling. Overexpression of either IEBP/hsp27 or ERE-BP in MCF-7 cells resulted in abnormal subcellular distribution of the IEBP/hsp27 and ERE-BP, with concomitant dysregulation of ERE occupancy as determined by chromatin immunoprecipitation. We hypothesize that IEBP/hsp27 and ERE-BP not only cause hormone resistance in New World primates but are also crucial to normal estrogen signaling in human cells. This appears to involve a physical association between the two proteins to form a complex that is able to interact with both E₂ and ER in cytosolic and nuclear compartments.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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