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This version published online on March 10, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0383
A more recent version of this article appeared on June 1, 2005
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Submitted on September 27, 2004
Accepted on March 3, 2005

Alternative Effects of the Ubiquitin-Proteasome Pathway on Glucocorticoid Receptor Downregulation and Transactivation are Mediated by CHIP, an E3 Ligase

Xinjia Wang and Donald B. DeFranco*

Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA

* To whom correspondence should be addressed. E-mail: dod1{at}pitt.edu.

The ubiquitin/proteasome-dependent protein degradation pathway (UPP) is responsible for the accelerated down-regulation of glucocorticoid receptor (GR) levels in cells subjected to chronic glucocorticoid exposure. While hormone-dependent down-regulation of GR operates in most cells, the receptor is not downregulated following long-term glucocorticoid treatment of either cultured embryonic hippocampal neurons or the HT22 hippocampal cell line. In this report we show that stable overexpression of the carboxy-terminus of hsp70-interacting protein (CHIP) E3 ligase can restore hormone-dependent down-regulation of GR in HT22 cells. Proteasome inhibitor studies establish that ubiquitylated GR can be efficiently engaged with the proteasome upon CHIP overexpression, unlike the case in parental HT22 cells. In addition to its impact on GR down-regulation, CHIP overexpression alters the coupling between the UPP and GR transactivation. Unlike other steroid receptors whose transactivation properties are typically reduced upon proteasome inhibition, GR transactivation in HT22 cells and other cell lines is enhanced upon proteasome inhibition. However, in HT22 cells overexpressing CHIP, proteasome inhibition leads to a reduction in GR transactivation activity. Thus, the divergent response of a single transactivator (i.e. GR) to the UPP can be dictated by CHIP, an E3 ligase that also functions as a proteasome targeting factor.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR
Ligands:   Dexamethasone



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