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Membrane Restraint of Estrogen Receptor Enhances Estrogen-Dependent Nuclear Localization and Genomic Function

Departments of Anesthesiology/Critical Care Medicine (Y.X., R.J.T., P.D.H., M.M.W.) and Neurology, Johns Hopkins University, Ross 364, Baltimore, Maryland 21287; and Department of Neurology (Y.X.), The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People’s Republic of China

Address all correspondence and requests for reprints to: Michael M. Wang, University of Michigan 7629 Medical Science II, Box 0622, Ann Arbor, Michigan 48109-0622. E-mail: micwang{at}umich.edu.

Estrogen receptor (ER) localizes to both the nucleus and the plasma membrane, mediating estrogen-dependent genomic and nongenomic signaling, respectively. In some cells, ER appears to be excluded from the nucleus, and it is unclear whether genomic signaling takes place. The purpose of this study was to determine whether membrane-associated ER is capable of genomic signaling, or whether this pool of receptors strictly serves membrane-mediated signaling. ER fused to the C-terminal cytoplasmic tail of bovine rhodopsin (Rh-ER) activates ER response element-dependent transcription only in the presence of estrogen; the activity is antagonized by the estrogen antagonist ICI 182,780 and by the dominant-negative mutant of ER and is unaffected by inhibitors of MAPKs and Akt signaling, indicating that this was due to direct genomic action. The activity of Rh-ER containing the activating Y537S mutation was also estrogen dependent, suggesting that estrogen gated the entry of Rh-ER into the nucleus. Indeed, cell fractionation studies demonstrated that Rh-ER protein, in contrast to ER that was nuclear at baseline, was excluded from the nucleus in the absence of hormone, and localized to the inner nuclear membrane on incubation with estrogen. These data demonstrate that membrane tethered ER is capable of nuclear function and that its transcriptional activity is regulated by hormone-dependent entry into the inner nuclear membrane. Furthermore, these experiments provide evidence that under certain circumstances, membrane proteins are capable of nuclear function without detectable nucleoplasmic localization.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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