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

Christopher C. Valley, Raphaël Métivier, Natalia M. Solodin, Amy M. Fowler, Mara T. Mashek, Lindsay Hill, Elaine T. Alarid

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

The ubiquitin-proteasome pathway has emerged as an important regulatory mechanism governing the activity of several transcription factors. While estrogen receptor α (ERα) 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 ERα proteolysis that is in turn necessary for its transcriptional activity. Here, we investigated the role of other regions of ERα and identified S118 within the N-terminal AF-1 transactivation domain as an additional element for regulating estrogen-induced ubiquitination and degradation of ERα. Significantly, different S118 mutants revealed that degradation and transcriptional activity of ERα are mechanistically separable functions of ERα. We find that proteolysis of ERα correlates with the ability of ERα 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 ERα proteolysis and transcription.

Original languageEnglish (US)
Pages (from-to)5417-5428
Number of pages12
JournalMolecular and cellular biology
Volume25
Issue number13
DOIs
StatePublished - Jul 1 2005

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Estrogen Receptors
Proteolysis
Estrogens
Ubiquitin
Proteasome Endopeptidase Complex
Transcriptional Activation
Transcription Factors
Furylfuramide
Ligands
Ubiquitination
Ligases
Genes

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Differential regulation of estrogen-inducible proteolysis and transcription by the estrogen receptor α N terminus. / Valley, Christopher C.; Métivier, Raphaël; Solodin, Natalia M.; Fowler, Amy M.; Mashek, Mara T.; Hill, Lindsay; Alarid, Elaine T.

In: Molecular and cellular biology, Vol. 25, No. 13, 01.07.2005, p. 5417-5428.

Research output: Contribution to journalArticle

Valley, Christopher C. ; Métivier, Raphaël ; Solodin, Natalia M. ; Fowler, Amy M. ; Mashek, Mara T. ; Hill, Lindsay ; Alarid, Elaine T. / Differential regulation of estrogen-inducible proteolysis and transcription by the estrogen receptor α N terminus. In: Molecular and cellular biology. 2005 ; Vol. 25, No. 13. pp. 5417-5428.
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