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J. Biol. Chem., Vol. 280, Issue 17, 17549-17561, April 29, 2005

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A Serine/Threonine-rich Motif Is One of Three Nuclear Localization Signals That Determine Unidirectional Transport of the Mineralocorticoid Receptor to the Nucleus^*

Rhian F. Walther, Ella Atlas¶, Amanda Carrigan, Yanouchka Rouleau, Allison Edgecombe¶, Laura Visentin||, Claudia Lamprecht¶, Gregory C. Addicks¶, Robert J. G. Haché¶||**, and Yvonne A. Lefebvre¶||

From the Departments of ^¶Medicine and ^||Biochemistry, Microbiology, and Immunology and the Graduate Program in Biochemistry, Ottawa Health Research Institute, Ottawa Hospital, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada

The mineralocorticoid receptor (MR) is a tightly regulated nuclear hormone receptor that selectively transmits corticosteroid signals. Steroid treatment transforms MR from a transcriptionally inert state, in which it is distributed equally between the nucleus and cytoplasm, to an active completely nuclear transcription factor. We report here that MR is an atypical nuclear hormone receptor that moves unidirectionally from the cytoplasm to the nucleus. We show that nuclear import of MR is controlled through three nuclear localization signals (NLSs) of distinct types. Nuclear localization of naïve MR was mediated primarily through a novel serine/threonine-rich NLS (NL0) in the receptor N terminus. Specific amino acid substitutions that mimicked phosphorylation selectively enhanced or repressed NL0 activity, highlighting the potential for active regulation of this new type of NLS. The second NLS (NL2) within the ligand-binding domain also lacks a recognizable basic motif. Nuclear transfer through this signal was strictly dependent on steroid agonist, but was independent of the interaction of MR with coactivator proteins. The third MR NLS (NL1) is a bipartite basic motif localized to the C terminus of the MR DNA-binding domain with properties distinct from those of NL1 of the closely related glucocorticoid receptor. NL1 acted in concert with NL0 and NL2 to stimulate nuclear uptake of the agonist-treated receptor, but also directed the complete nuclear localization of MR in response to treatment with steroid antagonist. These results present MR as a nuclear hormone receptor whose unidirectional transfer to the nucleus may be regulated through multiple pathways.

Received for publication, February 9, 2005

^* This work was supported in part by Operating Grant MOP 53142 from the Canadian Institutes of Health Research (to Y. A. L. and R. J. G. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a studentship from the Government of Ontario.

^** Investigator of the Canadian Institutes of Health Research. To whom correspondence should be addressed: Ottawa Health Research Inst., Ottawa Hospital, 725 Parkdale Ave., Ottawa, Ontario K1Y 4E9, Canada. Tel.: 613-761-5142; Fax: 613-761-5036; E-mail: rhache{at}ohri.ca.

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