The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions

Paul Webb, Phuong Nguyen, Cathleen Valentine, Gabriela N. Lopez, Grace R. Kwok, Eileen McInerney, Benita S. Katzenellenbogen, Eva Enmark, Jan Åke Gustafsson, Stefan Nilsson, Peter J. Kushner

Research output: Contribution to journalArticle

Abstract

Estrogen receptors (ERs α and β) enhance transcription in response to estrogens by binding to estrogen response elements (EREs) within target genes and utilizing transactivation functions (AF-1 and AF-2) to recruit p160 coactivator proteins. The ERs also enhance transcription in response to estrogens and antiestrogens by modulating the activity of the AP-1 protein complex. Here, we examine the role of AF-1 and AF-2 in ER action at AP-1 sites. Estrogen responses at AP-1 sites require the integrity of the ERα AF-1 and AF-2 activation surfaces and the complementary surfaces on the p160 coactivator GRIP1 (glucocorticoid receptor interacting protein 1), the NID/AF-1 region, and NR boxes. Thus, estrogen-liganded ERα utilizes the same protein-protein-contacts to transactivate at EREs and AP-1 sites. In contrast, antiestrogen responses are strongly inhibited by ERα AF-1 and weakly inhibited by AF-2. Indeed, ERα truncations that lack AF-1 enhance AP-1 activity in the presence of antiestrogens, but not estrogens. This phenotype resembles ERβ, which naturally lacks constitutive AF-1 activity. We conclude that the ERs enhance AP-1 responsive transcription by distinct mechanisms with different requirements for ER transactivation functions. We suggest that estrogen-liganded ER enhances AP-1 activity via interactions with p160s and speculate that antiestrogen-liganded ER enhances AP-1 activity via interactions with corepressors.

Original languageEnglish (US)
Pages (from-to)1672-1685
Number of pages14
JournalMolecular Endocrinology
Volume13
Issue number10
DOIs
StatePublished - Jan 1 1999

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Webb, P., Nguyen, P., Valentine, C., Lopez, G. N., Kwok, G. R., McInerney, E., Katzenellenbogen, B. S., Enmark, E., Gustafsson, J. Å., Nilsson, S., & Kushner, P. J. (1999). The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Molecular Endocrinology, 13(10), 1672-1685. https://doi.org/10.1210/mend.13.10.0357