Protein 14-3-3σ interacts with and favors cytoplasmic subcellular localization of the glucocorticoid receptor, acting as a negative regulator of the glucocorticoid signaling pathway

Tomoshige Kino, Emanuel Souvatzoglou, Massimo U. De Martino, Maria Tsopanomihalu, Yihong Wan, George P. Chrousos

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The glucocorticoid receptor (GR) α 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 GRα in a cell line replete with or devoid of 14-3-3σ. We found that endogenous 14-3-3σ helped localize green fluorescent proteinfused GRα in the cytoplasm in the absence of ligand and potentiated its nuclear export after ligand withdrawal. 14-3-3σ also suppressed the transcriptional activity of GRα on a glucocorticoid-responsive promoter. Disruption of the classic nuclear export signal of 14-3-3σ inactivated its ability to influence the nucleocytoplasmic trafficking and transactivation activity of GRα, whereas introduction of a mutation inactivating the binding activity of 14-3-3σ to some of its partner proteins did not. 14-3-3σ bound the ligand-binding domain of GRα through its COOH-terminal portion, in a partially ligand-dependent fashion, while it did not interact with "ligand-binding domain" of GRβ at all. These results suggest that 14-3-3σ 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 GRα. Conversely, through its 14-3-3 protein interactions, GRα may influence these processes.

Original languageEnglish
Pages (from-to)25651-25656
Number of pages6
JournalJournal of Biological Chemistry
Issue number28
Publication statusPublished - 11 Jul 2003
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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