Abstract
Most studies have reported an up-regulation of retinoic acid receptor (RAR) mRNA expression by all-trans retinoic acid (RA). We aimed to study the effect of RA on RAR protein levels in MCF-7 human breast cancer cells. Incubation of these cells with 10-6 M RA induced a rapid breakdown of both RARα and RARγ in spite of the accumulation of their mRNAs. Proteasome specific inhibitors blocked the RA-induced breakdown of RARs. Furthermore, RA enhanced the formation of the complex between RARα and ubiquitin in a concentration- and time-dependent manner, suggesting the involvement of ubiquitin and proteasome in this reaction. Retinoid X receptor α (RXRα) was also decreased, albeit to a lesser extent, in RA-treated cells. Use of synthetic receptor agonists and antagonists clearly showed that the effect of the retinoid on the breakdown of the retinoid receptors is receptor-ligand agonist-dependent and blunted by the antagonist. An electrophoretic mobility shift assay, using nuclear extracts from RA-treated cells, showed that a reduction in complex formation with hormone response elements correlated with the reduction of RAR and RXR protein. These data suggest that RA induces the breakdown of RARs through a process involving ubiquitination and that this phenomenon causes a reduction in the formation of DNA-receptor complexes.
Original language | English (US) |
---|---|
Pages (from-to) | 1347-1355 |
Number of pages | 9 |
Journal | Biochemical Pharmacology |
Volume | 61 |
Issue number | 11 |
DOIs | |
State | Published - Jun 1 2001 |
Externally published | Yes |
Keywords
- Proteasomes
- Proteolysis
- Retinoic acid
- Retinoic acid receptor
- Ubiquitination
ASJC Scopus subject areas
- Biochemistry
- Pharmacology