Ubiquitinated or sumoylated retinoic acid receptor α determines its characteristic and interacting model with retinoid X receptor α in gastric and breast cancer cells

Abstract

Retinoic acid receptor α (RARα) plays an important role in mediating all-trans retinoic acid (ATRA) signals. In this study, we found that ATRA up-regulated RARα mRNA and protein expression in gastric cancer BGC-823 cells. However, in breast cancer MCF-7 cells it down-regulated RARα protein expression with no effect on its RARα mRNA. Immunoprecipitation/Western blot analysis showed that, although sumoylated and ubiquitinated RARα existed simultaneously in both cancer cell lines, ATRA exerted different regulatory effects on sumoylation and ubiquitination of RARα. In MCF-7 cells, ATRA treatment enhanced the ubiquitination of RARα and the subsequent degradation of RARα through the ubiquitin/proteasome pathway. This resulted in a reduction in the DNA binding activity of RARα/retinoid X receptor α (RXRα) heterodimer, the separation of RXRα from RARα and the translocation of RXRα from the nucleus to the cytoplasm. By contrast, in BGC-823 cells, ATRA augmented sumoylation, not ubiquitination, of RARα. The stability of sumoylated RARα was significantly stronger than in non-sumoylated RARα. These results also showed an increase in the DNA binding activity of the RARα/RXRα heterodimer and the stability of nuclear localization of this heterodimer, which normally facilitates the ATRA signal transduction. In conclusion, our results reveal a novel mechanism for the regulation of RARα-dependent signal transduction through the ubiquitin/proteasome pathway in breast cancer cells and the sumoylation pathway in gastric cancer cells. © 2004 Society for Endocrinology.