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

Abstract

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

• Authors: Qiao Wu, Xiao-feng Lin, Xiao-feng Ye, Bing Zhang, Zhong Xie, Wen-jin Su
• Journal: Journal of molecular endocrinology (J Mol Endocrinol) Vol. 32 Issue 3 Pg. 595-613 (Jun 2004) ISSN: 0952-5041 [Print] England
• PMID: 15171703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proteasome Inhibitors
• RARA protein, human
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• Retinoid X Receptor alpha
• SUMO-1 Protein
• Polyubiquitin
• Tretinoin
• Proteasome Endopeptidase Complex

Topics

• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Dimerization
• Female
• Humans
• Polyubiquitin (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors
• Protein Processing, Post-Translational
• Receptors, Retinoic Acid (chemistry, genetics, metabolism)
• Retinoic Acid Receptor alpha
• Retinoid X Receptor alpha (chemistry, genetics, metabolism)
• SUMO-1 Protein (metabolism)
• Stomach Neoplasms (metabolism)
• Tretinoin (metabolism)