9-cis-retinoic acid decreases the level of its cognate receptor, retinoid X receptor, through acceleration of the turnover

In this study, we investigated the ligand-mediated regulation of retinoid X receptor (RXR) in two human cell lines (HepG2 and JEG-3 cells), which have been reported to express RXR alpha predominantly. Western blot analysis revealed that a treatment with 1 mu M 9-cis-retinoic acid (9-cis RA) for 24 h decreased RXR alpha protein level to 72 +/- 9 and 75 +/- 7% in HepG2 and JEG-3 cells, respectively, when the levels in the non-treated cells were expressed as 100%. The decrease was not due to the changes in steady-state level of RXR alpha mRNA or its stability as revealed by Northern blot analysis. However, the 9-cis RA treatment decreased the half-life of RXR alpha protein as determined by pulse-chase analysis. It was thus demonstrated that 9-cis RA downregulates RXR alpha by increasing the turnover of the protein in the two cell lines. The ligand-dependent downregulation of RXR alpha protein may be important for several hormonal signalings, in which the receptors heterodimerize with RXR. (C) 1999 Academic Press.