title: The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions.
abstract: Estrogen receptors (ERs alpha and beta) 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 ERalpha 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 ERalpha utilizes the same protein-protein contacts to transactivate at EREs and AP-1 sites. In contrast, antiestrogen responses are strongly inhibited by ERalpha AF-1 and weakly inhibited by AF-2. Indeed, ERalpha truncations that lack AF-1 enhance AP-1 activity in the presence of antiestrogens, but not estrogens. This phenotype resembles ERbeta, 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.
authors.affiliation: Metabolic Research Unit, University of California School of Medicine, San Francisco 94143, USA.
authors.forename: P
authors.initials: P
authors.lastname: Webb
authors.forename: P
authors.initials: P
authors.lastname: Nguyen
authors.forename: C
authors.initials: C
authors.lastname: Valentine
authors.forename: G N
authors.initials: GN
authors.lastname: Lopez
authors.forename: G R
authors.initials: GR
authors.lastname: Kwok
authors.forename: E
authors.initials: E
authors.lastname: McInerney
authors.forename: B S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: E
authors.initials: E
authors.lastname: Enmark
authors.forename: J A
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: S
authors.initials: S
authors.lastname: Nilsson
authors.forename: P J
authors.initials: PJ
authors.lastname: Kushner
mesh_terms: D001665:Binding Sites; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D010641:Phenotype; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D017384:Sequence Deletion; D012694:Serine; D013629:Tamoxifen / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D020845:Selective Estrogen Receptor Modulators; D018808:Transcription Factor AP-1; D013629:Tamoxifen; D012694:Serine; D004958:Estradiol