Differential regulation of estrogen-inducible proteolysis and transcription by the estrogen receptor alpha N terminus.
The ubiquitin-proteasome pathway has emerged as an important regulatory mechanism governing the activity of several transcription factors. While estrogen receptor alpha (ERalpha) is also subjected to rapid ubiquitin-proteasome degradation, the relationship between proteolysis and transcriptional regulation is incompletely understood. Based on studies primarily focusing on the C-terminal ligand-binding and AF-2 transactivation domains, an assembly of an active transcriptional complex has been proposed to signal ERalpha proteolysis that is in turn necessary for its transcriptional activity. Here, we investigated the role of other regions of ERalpha and identified S118 within the N-terminal AF-1 transactivation domain as an additional element for regulating estrogen-induced ubiquitination and degradation of ERalpha. Significantly, different S118 mutants revealed that degradation and transcriptional activity of ERalpha are mechanistically separable functions of ERalpha. We find that proteolysis of ERalpha correlates with the ability of ERalpha mutants to recruit specific ubiquitin ligases regardless of the recruitment of other transcription-related factors to endogenous model target genes. Thus, our findings indicate that the AF-1 domain performs a previously unrecognized and important role in controlling ligand-induced receptor degradation which permits the uncoupling of estrogen-regulated ERalpha proteolysis and transcription.
Valley
Christopher C
CC
Department of Physiology, 1300 University Ave., 120 SMI, University of Wisconsin--Madison, Madison, Wisconsin 53706, USA.
Métivier
Raphaël
R
Solodin
Natalia M
NM
Fowler
Amy M
AM
Mashek
Mara T
MT
Hill
Lindsay
L
Alarid
Elaine T
ET
D000595:Amino Acid Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D000077267:Fulvestrant; D005786:Gene Expression Regulation; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008024:Ligands; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D025801:Ubiquitin; D000077267:Fulvestrant; D000431:Ethanol; D012694:Serine; D004958:Estradiol