12
Views
40
CrossRef citations to date
0
Altmetric
Transcriptional Regulation

Ligand-Dependent Degradation of Retinoid X Receptors Does Not Require Transcriptional Activity or Coactivator Interactions

, , &
Pages 4909-4918 | Received 13 Dec 2000, Accepted 01 May 2001, Published online: 28 Mar 2023
 

Abstract

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.

ACKNOWLEDGMENTS

We thank M. Manchester and D. Chakravarti for comments on the manuscript and the medicinal chemistry department at Ligand Pharmaceuticals for providing LGD1069, LGD1268, and LG100754.

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 61.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 265.00 Add to cart

* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.