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Originally published In Press as doi:10.1074/jbc.M302818200 on May 1, 2003

J. Biol. Chem., Vol. 278, Issue 28, 25651-25656, July 11, 2003
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Protein 14-3-3{sigma} Interacts with and Favors Cytoplasmic Subcellular Localization of the Glucocorticoid Receptor, Acting as a Negative Regulator of the Glucocorticoid Signaling Pathway*

Tomoshige Kino {ddagger} §, Emanuel Souvatzoglou {ddagger}, Massimo U. De Martino {ddagger}, Maria Tsopanomihalu ¶, Yihong Wan || and George P. Chrousos {ddagger}

From the {ddagger}Pediatric and Reproductive Endocrinology Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, the Human Retrovirus Section, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, and the ||Department of Pathology and Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado 80262

The glucocorticoid receptor (GR) {alpha} interacts with the highly conserved 14-3-3 family proteins. The latter bind phosphorylated serine/threonine residues of "partner" molecules and influence many signal transduction events by altering their subcellular localization and/or protecting them from proteolysis. To examine the physiologic role of 14-3-3 on the glucocorticoid-signaling pathway, we studied the nucleocytoplasmic shuttling and transactivation properties of GR{alpha} in a cell line replete with or devoid of 14-3-3{sigma}. We found that endogenous 14-3-3{sigma} helped localize green fluorescent protein-fused GR{alpha} in the cytoplasm in the absence of ligand and potentiated its nuclear export after ligand withdrawal. 14-3-3{sigma} also suppressed the transcriptional activity of GR{alpha} on a glucocorticoid-responsive promoter. Disruption of the classic nuclear export signal of 14-3-3{sigma} inactivated its ability to influence the nucleocytoplasmic trafficking and transactivation activity of GR{alpha}, whereas introduction of a mutation inactivating the binding activity of 14-3-3{sigma} to some of its partner proteins did not. 14-3-3{sigma} bound the ligand-binding domain of GR{alpha} through its COOH-terminal portion, in a partially ligand-dependent fashion, while it did not interact with "ligand-binding domain" of GR{beta} at all. These results suggest that 14-3-3{sigma} functions as a negative regulator in the glucocorticoid signaling pathway, possibly by shifting the subcellular localization/circulation of this receptor toward the cytoplasm through its nuclear export signal. Since 14-3-3 proteins play significant roles in numerous cellular activities, such as cell cycle progression, growth, differentiation, and apoptosis, these actions might indirectly influence the transcriptional activity of GR{alpha}. Conversely, through its 14-3-3 protein interactions, GR{alpha} may influence these processes.

Received for publication, March 19, 2003 , and in revised form, April 25, 2003.

* 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.

§ To whom correspondence should be addressed: Pediatric and Reproductive Endocrinology Branch, NICHD, NIH, Bldg. 10, Rm. 9D42, 10 Center Dr., MSC 1583, Bethesda, MD 20892-1583. Tel.: 301-496-6417; Fax: 301-480-2024; E-mail: kinot{at}mail.nih.gov.


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