Differential regulation of estrogen-inducible proteolysis and transcription by the estrogen receptor α N terminus

The ubiquitin-proteasome pathway has emerged as an important regulatory mechanism governing the activity of several transcription factors. While estrogen receptor a ER alpha 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-terminall ligand-binding and AF-2 transactivation domains, an assembly of an active transcriptional complex has been proposed to signal ER alpha proteolysis that is in turn necessary for its transcriptional activity. Here, we investigated the role of other regions of ER alpha and identified S118 within the N-terminal AF-1 transactivation domain as an additional element for regulating estrogen-induced ubiquitination and degradation of ER alpha. Significantly, different S118 mutants revealed that degradation and transcriptional activity of ER alpha are mechanistically separable functions of ER alpha. We find that proteolysis of ER alpha correlates with the ability of ER alpha 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 ER alpha proteolysis and transcription.