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This version published online on October 23, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0262
Molecular Endocrinology Vol. 0, No. 2003 200302621-
doi:10.1210/me.2003-0262
Copyright © 2003 by the Endocrine Society.
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Submitted on July 7, 2003
Accepted on October 16, 2003

Membrane restraint of estrogen receptor {alpha} enhances estrogen dependent nuclear localization and genomic function

Yun Xu1, Richard J. Traystman1, Patricia D. Hurn1, and Michael M. Wang1*

1 Departments of Anesthesiology/Critical Care Medicine and Neurology, Johns Hopkins University, Ross 364, 600 N. Wolfe St., Baltimore, MD 21287; Department of Neurology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, P.R. China

* To whom correspondence should be addressed. E-mail: micwang{at}umich.edu.

ER{alpha} localizes to both the nucleus and the plasma membrane, mediating estrogen dependent genomic and non-genomic signaling, respectively. In some cells, ER{alpha} 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{alpha} is capable of genomic signaling, or whether this pool of receptors strictly serves membrane-mediated signaling. ER{alpha} fused to the C-terminal cytoplasmic tail of bovine rhodopsin (Rh-ER{alpha}) activates estrogen response element (ERE)-dependent transcription only in the presence of estrogen; the activity is antagonized by the estrogen antagonist ICI182,780 and by the dominant negative mutant of ER{alpha} and is unaffected by inhibitors of MAP kinases and Akt signaling, indicating that this was due to direct genomic action. The activity of Rh-ER{alpha} containing the activating Y537S mutation was also estrogen dependent, suggesting that estrogen gated the entry of Rh-ER{alpha} into the nucleus. Indeed, cell fractionation studies demonstrated that Rh-ER{alpha} protein, in contrast to ER{alpha} which 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{alpha} 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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