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J. Biol. Chem., Vol. 278, Issue 52, 52511-52518, December 26, 2003

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The Co-repressor Hairless Protects ROR Orphan Nuclear Receptor from Proteasome-mediated Degradation^*

Anna N. Moraitis and Vincent Giguère

From the Molecular Oncology Group, McGill University Health Center and the Departments of Biochemistry, Medicine, and Oncology, McGill University, Montréal, Québec H3A 1A1, Canada

ROR is a constitutively active orphan nuclear receptor essential for cerebellar development and is previously shown to regulate genes involved in both myogenesis and adipogenesis. The transcriptional activity of ROR is dependent on the presence of a ubiquitous ligand and can be abolished by interaction with Hairless (Hr), a ligand-oblivious nuclear receptor co-repressor. In this study, we first demonstrate that ROR is a short-lived protein and that treatment with the MG-132 proteasome inhibitor results in the accumulation of ubiquitin-conjugated receptor and inhibition of transcription. These data show that ROR transcriptional activity and degradation are intrinsically linked. In addition, the introduction of inactivation mutations in the ligand-binding pocket and co-regulator-binding surface of ROR significantly increases protein stability, indicating that ligand and/or co-regulator binding perpetuates ROR degradation. Strikingly, expression of the co-repressor Hr results in the stabilization of ROR because of an inhibition of proteasome-mediated degradation of the receptor. Stabilization of ROR by Hr requires intact nuclear receptor recognition LXXLL motifs within Hr. Interestingly, the co-repressor nuclear receptor co-repressor (NCoR) has no effect on ROR protein turnover. This study shows that stabilization of ROR is an essential component of Hr-mediated repression and suggests a molecular mechanism to achieve transcriptional repression by a liganded receptor-co-repressor complex.

Received for publication, July 25, 2003 , and in revised form, October 16, 2003.

^* This work was supported by the Canadian Institutes of Health Research. 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.

To whom correspondence should be addressed: Molecular Oncology Group, McGill University Health Centre, Rm. H5–21, 687 Pine Ave. West, Montréal, PQ H3A 1A1, Canada. Tel.: 514-843-1406; Fax: 514-843-1478; E-mail: vincent.giguere{at}mcgill.ca.

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