title: Regulation of estrogen receptor activation of the prolactin enhancer/promoter by antagonistic activation function-2-interacting proteins.
abstract: Transcriptional responses to estrogens are controlled by the cell- and gene-specific interactions of the nuclear estrogen receptor (ER) with cofactors and other transcription factors. The pituitary-specific PRL enhancer/promoter is regulated by estrogens only when it is bound by both ER and the pituitary-specific transcription factor, Pit-1. Cooperative ER/Pit-1 activation of the dormant PRL enhancer/promoter in pituitary progenitor cells requires the estrogen-dependent activation function-2 (AF-2) of ER, but is inhibited by one AF-2-interacting cofactor, RIP140. Here, the complex actions of RIP140 and other AF-2-interacting proteins at the PRL enhancer/promoter were shown to operate via ER itself. RIP140 inhibition of ER/Pit-1 activation in the absence of AF-1 and RIP140 inhibition of both ER alpha and ER beta cooperative activation with Pit-1 suggested a conserved ER site for RIP140 action, possibly AF-2. Coexpression of other AF-2-interacting proteins, including the p160 factors, steroid receptor coactivator-1a (SRC-1a) and glucocorticoid receptor interacting protein-1 (GRIP1), had negligible effects on ER alpha/Pit-1 cooperative activation, but partially relieved RIP140 inhibition. Relief of RIP140 inhibition required the AF-2-binding, LXXLL motifs in SRC-1a and GRIP1. An ER AF-2 mutant that selectively blocked ER interaction with p160s, but not RIP140, still cooperated with Pit-1 and was inhibited by RIP140, but was not relieved by SRC-1a or GRIP1 expression. Thus, SRC-1a and GRIP1 binding to AF-2 counteracted the inhibition of ER/Pit-1 activation by another AF-2-interacting protein, RIP140. Complex, sometimes antagonistic, actions of different classes of AF-2-interacting proteins may play an important role in the cell- and gene-specific estrogen regulation of PRL and other genes.
authors.affiliation: Metabolic Research Unit, University of California, San Francisco 94143-0540, USA. freds@metabolic.ucsf.edu
authors.forename: F
authors.initials: F
authors.lastname: Schaufele
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D050882:CREB-Binding Protein; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D047629:Estrogen Receptor beta; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D000078723:Nuclear Receptor Interacting Protein 1; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011388:Prolactin / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins; D047629:Estrogen Receptor beta; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D000078723:Nuclear Receptor Interacting Protein 1; D011388:Prolactin; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D015534:Trans-Activators; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C498002:Ncoa2 protein, mouse; C494185:Pou1f1 protein, mouse; C494364:Crebbp protein, mouse; C538861:Ncoa1 protein, mouse