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Sumoylation of the Estrogen Receptor Hinge Region Regulates Its Transcriptional Activity

Institut National de la Santé et de la Recherche Médicale, Unité 590, Centre Léon Bérard, 69373 Lyon Cedex 08, France

Address all correspondence and requests for reprints to: Laura Corbo, Unité Institut National de la Santé et de la Recherche Médicale, Unité 590, Centre Léon Bérard, 28 Rue Laennec, 69373 Lyon Cedex 08, France. E-mail: corbo{at}lyon.fnclcc.fr.

The steroid hormone 17ß-estradiol (estrogen) plays a significant role in the normal physiology of the mammary gland and breast cancer development primarily through binding to its receptor, the estrogen receptor (ER). ER is a nuclear transcription factor undergoing different types of posttranslational modifications, i.e. phosphorylation, acetylation, and ubiquitination, which regulate its transcriptional activation and/or stability. Here we identify ER as a new target for small ubiquitin-like modifier (SUMO)-1 modification in intact cells and in vitro. Moreover, ER sumoylation occurs strictly in the presence of hormone. SUMO-1 appears to regulate ER-dependent transcription. Using a series of mutants, we demonstrated that ER is sumoylated at conserved lysine residues within the hinge region. Mutations that prevented SUMO modification impaired ER-induced transcription without influencing ER cellular localization. In addition to identifying protein inhibitor of activated signal transducer and activator of transcription (PIAS)1 and PIAS3 as E3 ligases for ER, we also found that PIAS1 and PIAS3, as well as Ubc9, modulated ER-dependent transcription independently from their SUMO-1 conjugation activity. These findings identify sumoylation as a new mechanism modulating ER-dependent cellular response and provide a link between the SUMO and estrogen pathways.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   PIAS1  |  PIAS3

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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