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J. Biol. Chem., Vol. 278, Issue 28, 25651-25656, July 11, 2003
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Protein 14-3-3
Interacts with and Favors Cytoplasmic Subcellular Localization of the Glucocorticoid Receptor, Acting as a Negative Regulator of the Glucocorticoid Signaling Pathway*
From the
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) 
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 in a
cell line replete with or devoid of 14-3-3
. We found that endogenous
14-3-3 helped localize green fluorescent protein-fused GR in the
cytoplasm in the absence of ligand and potentiated its nuclear export after
ligand withdrawal. 14-3-3 also suppressed the transcriptional activity
of GR on a glucocorticoid-responsive promoter. Disruption of the
classic nuclear export signal of 14-3-3 inactivated its ability to
influence the nucleocytoplasmic trafficking and transactivation activity of
GR, whereas introduction of a mutation inactivating the binding
activity of 14-3-3 to some of its partner proteins did not.
14-3-3 bound the ligand-binding domain of GR through its
COOH-terminal portion, in a partially ligand-dependent fashion, while it did
not interact with "ligand-binding domain" of GR
at all.
These results suggest that 14-3-3 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. Conversely, through its 14-3-3 protein
interactions, GR 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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