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Role of 14-3-3 as a Positive Regulator of the Glucocorticoid Receptor Transcriptional Activation

School of Life Sciences and Biotechnology, Korea University (Y.S.K., S.-W.J., H.J.S., J.K.), Seoul 136-701; Graduate School of Biotechnology, Kyung Hee University (S.-W.J.), Yongin 449-701; Department of Biomedical Laboratory Science, College of Health Science, Yonsei University (H.J.S.), Wonju 222-701; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine (H.J.L., D.S.N.), Seoul 138-736; and Department of Clinical Laboratory Science, School of Medicine, Eulji University (I.S.K.), Daejun 301-832, South Korea

Address all correspondence and requests for reprints to: Dr. Jesang Ko, School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 136-701, South Korea. E-mail: jesangko{at}korea.ac.kr.

The glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, mediates the effects of glucocorticoids. It is known that 14-3-3 family proteins interact with GR and regulate its transcriptional activity. They also bind to several molecules and influence many cellular events by altering their subcellular localization and/or acting as a chaperone. Recently, it has been proposed that ligand-activated degradation of GR occurs via the ubiquitin-proteasomal degradation pathway and that inhibition of proteasomal activity induces up-regulation of GR and enhances the transcriptional activity of GR. To examine the function of 14-3-3 in the glucocorticoid-dependent signal pathway, we studied the regulatory role of 14-3-3 in ligand-induced GR transcriptional activation. 14-3-3 Enhanced the transcriptional activity of GR, and the levels of GR were higher in cells transfected with the 14-3-3 expression vector in response to glucocorticoid. The GR level increased in both cytosol and nucleus, and endogenous GR was also elevated by 14-3-3 in HeLa cells. 14-3-3 Inhibited ligand-induced down-regulation of GR. Proteasomal inhibition did not induce any synergistic effect on the 14-3-3-induced increase in GR in response to glucocorticoid, and inhibition of translation did not block elevation of GR by 14-3-3, indicating that 14-3-3 induces stabilization of GR. These results suggest that 14-3-3 functions as a positive regulator in the glucocorticoid signal pathway by blocking the degradation of GR and inducing an elevation of GR, thus enhancing the transcriptional activity of GR.