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

AUTOR(ES)

Osburn, Deborah L.

FONTE

American Society for Microbiology

RESUMO

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.

Documentos Relacionados

• The yeast Ada complex mediates the ligand-dependent activation function AF-2 of retinoid X and estrogen receptors
• Recombinant thyroid hormone receptor and retinoid X receptor stimulate ligand-dependent transcription in vitro.
• Differential ligand-dependent protein–protein interactions between nuclear receptors and a neuronal-specific cofactor
• Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin
• TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors.