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J. Biol. Chem., Vol. 280, Issue 12, 11120-11126, March 25, 2005

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Stabilization of the Unliganded Glucocorticoid Receptor by TSG101^*

Naima Ismaili, Raymond Blind, and Michael J. Garabedian

From the Departments of Microbiology and Urology, New York Univeristy Cancer Institute, New York University School of Medicine, New York, New York 10016

The glucocorticoid receptor (GR) has been shown to undergo hormone-dependent down-regulation via transcriptional, post-transcriptional, and posttranslational mechanisms. However, the mechanisms involved in modulating GR levels in the absence of hormone remain enigmatic. Here we demonstrate that TSG101, a previously identified GR-interacting protein, stabilizes the hypophosphorylated form of GR in the absence of ligand. We found that a non-phosphorylated version of GR (S203A/S211A) showed enhanced interaction with TSG101 as compared with the wild type GR, suggesting that TSG101 interacts more favorably with GR when it is not phosphorylated. A significant accumulation of GR S203A/S211A protein is detected in the absence of ligand when TSG101 is overexpressed, whereas no increase in the wild type phosphorylated GR or phosphomimetic GR S203E/S211E was observed in mammalian cells. In contrast, down-regulation of TSG101 expression by siRNA renders the hypophosphorylated form of GR unstable. We further show that TSG101 stabilizes GR by impeding its degradation by the proteasome and extending receptor half-life. Thus, in absence of a ligand, TSG101 binds GR and protects the non-phosphorylated receptor from degradation.

Received for publication, January 3, 2005 , and in revised form, January 12, 2005.

^* This work was supported by grants from the National Institutes of Health and the ACS (to M. J. G.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

To whom correspondence should be addressed: Dept. of Microbiology, NYU School of Medicine, 550 First Ave., New York, NY 10016. Tel.: 212-263-7662; Fax: 212-263-8276; E-mail: garabm01{at}med.nyu.edu.

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