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Molecular and Cellular Biology, August 2001, p. 4909-4918, Vol. 21, No. 15
Nuclear Receptor Discovery, Ligand
Pharmaceuticals, San Diego, California 92121
Received 13 December 2000/Returned for modification 31 December
2000/Accepted 1 May 2001
Cells utilize ubiquitin-mediated proteolysis to regulate the
activity of numerous proteins involved in signal transduction, cell
cycle control, and transcriptional regulation. For a number of
transcription factors, there appears to be a direct correlation between
transcriptional activity and protein instability, suggesting that cells
use targeted destruction as one method to down-regulate or attenuate
gene expression. In this report we demonstrate that retinoid X
receptors (RXRs) which function as versatile mediators of nuclear
hormone-dependent gene expression are marked for destruction upon
binding agonist ligands. Interestingly, when RXR serves as a
heterodimeric partner for retinoic acid (RAR) or thyroid hormone (TR)
receptors, binding of agonists by RAR or TR leads to degradation of
both the transcriptionally active RAR or TR subunits as well as the
transcriptionally inactive RXR subunit. Furthermore, using a series of
mutants in the ligand-dependent activation domain (activation function
2), we demonstrate that agonist-stimulated degradation of RXR does not
require corepressor release, coactivator binding, or transcriptional
activity. Taken together, the data suggest a model for targeted
destruction of transcription factors based on structural or
conformational signals as opposed to functional coupling with gene transcription.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.15.4909-4918.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Ligand-Dependent Degradation of Retinoid X
Receptors Does Not Require Transcriptional Activity or
Coactivator Interactions

and
*
Corresponding author. Present address: X-Ceptor
Therapeutics, 4757 Nexus Center Dr., Suite 200, San Diego, CA 92121. Phone: (858) 458-4542. Fax: (858) 458-4501. E-mail:
ischulman{at}x-ceptor.com.
Present address: X-Ceptor Therapeutics, San Diego, CA 92121.
Present address: Dupont Pharmaceutical Research Laboratories, San
Diego, CA 92121.
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