Involvement of suppressor for Gal 1 in the ubiquitin/proteasome-mediated degradation of estrogen receptors.
The proteasome-mediated pathway involves the degradation of several nuclear receptors. Previously we demonstrated that the interaction between the suppressor for Gal 1 (SUG1) and nuclear receptors, the vitamin D receptor, or the pregnane X receptor was involved in proteasome-mediated degradation. In our recent experiments, we examined the potential role of SUG1 in the proteasome-mediated degradation of estrogen receptors (ER)alpha and -beta. Both ERs interacted with SUG1 in a ligand-dependent manner. Functionally, the overexpression of SUG1 inhibited both ERalpha- and ERbeta-mediated transcription in the presence of ligands. Transient expression studies demonstrated that the overexpression of wild-type SUG1 generated proteolytic fragments of both ERs and that these products were blocked by a proteasome inhibitor. The overexpression of SUG1 also enhanced the formation of ubiquitinated proteins of both ERs in the presence of ligand. On the other hand, bisphenol A (BSA), which activated ER-mediated transcription, did not enhance the interaction between ERbeta and SUG1. Furthermore, the degradation of ERbeta was much slower in the presence of BSA than in the presence of estradiol or phthalate, which is another endocrine-disrupting chemical. Also, BSA had no effect on the formation of proteolytic fragments of ERbeta, and neither did it have any effect on the ubiquitination of ERbeta. These findings indicate that the ubiquitin/proteasome-mediated degradation of both ER proteins may involve the interaction of SUG1 with both ERs. Moreover, BSA strongly blocked the ubiquitination and degradation of ERbeta compared with estradiol, suggesting that BSA may affect the ERbeta-mediated transcription of target genes by inhibiting ERbeta degradation.
Masuyama
Hisashi
H
Department of Obstetrics and Gynecology, Okayama University Medical School, 2-5-1 Shikata, Okayama 700-8558, Japan. masuyama@cc.okayama-u.ac.jp
Hiramatsu
Yuji
Y
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008024:Ligands; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D000077297:Pregnane X Receptor; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism; D000098826:Bisphenol A Compounds
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D001559:Benzhydryl Compounds; D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008024:Ligands; D009097:Multienzyme Complexes; D010636:Phenols; D000077297:Pregnane X Receptor; D046988:Proteasome Endopeptidase Complex; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011987:Receptors, Steroid; D014157:Transcription Factors; D025801:Ubiquitin; D001616:beta-Galactosidase; C092282:PSMC5 protein, human; C106843:SUG1 protein, mammalian; C006780:bisphenol A; D000098826:Bisphenol A Compounds