Role of 14-3-3 eta as a positive regulator of the glucocorticoid receptor transcriptional activation.
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 14-3-3eta in the glucocorticoid-dependent signal pathway, we studied the regulatory role of 14-3-3eta in ligand-induced GR transcriptional activation. 14-3-3eta Enhanced the transcriptional activity of GR, and the levels of GR were higher in cells transfected with the 14-3-3eta expression vector in response to glucocorticoid. The GR level increased in both cytosol and nucleus, and endogenous GR was also elevated by 14-3-3eta in HeLa cells. 14-3-3eta Inhibited ligand-induced down-regulation of GR. Proteasomal inhibition did not induce any synergistic effect on the 14-3-3eta-induced increase in GR in response to glucocorticoid, and inhibition of translation did not block elevation of GR by 14-3-3eta, indicating that 14-3-3eta induces stabilization of GR. These results suggest that 14-3-3eta 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.
Kim
Yoon Suk
YS
School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 136-701, South Korea.
Jang
Sung-Wuk
SW
Sung
Ho Joong
HJ
Lee
Hye Jin
HJ
Kim
In Sik
IS
Na
Doe Sun
DS
Ko
Jesang
J
D048948:14-3-3 Proteins / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004355:Drug Stability; D005938:Glucocorticoids / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D048948:14-3-3 Proteins; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone