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The regulatory role of estrogen, bone morphogenetic protein-4 (BMP-4), and TGF-β has a strong impact on hormone secretion, gene transcription, and cellular growth of prolactin (PRL)-producing cells. In contrast to TGF-β, BMP-4 induces the secretion of PRL in GH3 cells. Therefore, we studied the mechanism of their transcriptional regulation. Both BMP-4 and TGF-β inhibited the transcriptional activity of the estrogen receptor (ER). Estrogens had no effect on TGF-β-specific Smad protein transcriptional activity but presented a stimulatory action on the transcriptional activity of the BMP-4-specific Smads. BMP-4/estrogen cross talk was observed both on PRL hormone secretion and on the PRL promoter. This cross talk was abolished by the expression of a dominant-negative form for Smad-1 and treatment with ICI 182780 but not by point mutagenesis of the estrogen response element site within the promoter, suggesting that Smad/ER interaction might be dependent on the ER and a Smad binding element. By serial deletions of the PRL promoter, we observed that indeed a region responsive to BMP-4 is located between -2000 and -1500 bp upstream of the transcriptional start site. Chromatin immunoprecipitation confirmed Smad-4 binding to this region, and by specific mutation and gel shift assay, a Smad binding element responsible site was characterized. These results demonstrate that the different transcriptional factors involved in the Smad/ER complexes regulate their transcriptional activity in differential ways and may account for the different regulatory roles of BMP-4, TGF-β, and estrogens in PRL-producing cells. Copyright © 2009 by The Endocrine Society.


Documento: Artículo
Título:Molecular interaction of BMP-4, TGF-β, and estrogens in lactotrophs: Impact on the PRL promoter
Autor:Giacomini, D.; Páez-Pereda, M.; Stalla, J.; Stalla, G.K.; Arzt, E.
Filiación:Laboratorio de Fisiología Y Biología Molecular, Departamento de Fisiología, Biología Molecular Y Celular, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina
Max-Planck Institute of Psychiatry, 80804 Munich, Germany
Affectis Pharmaceuticals, 82152 Martinsried, Germany
Laboratorio Fisiología Y Biología Molecular, Departamento de Fisiología, Biología Molecular Y Celular, Pabellon II, 1428 Buenos Aires, Argentina
Palabras clave:bone morphogenetic protein 4; estrogen; estrogen receptor; fulvestrant; prolactin; Smad protein; Smad1 protein; transforming growth factor beta; animal cell; article; binding site; chromatin immunoprecipitation; controlled study; estrogen responsive element; gene mutation; hormone release; mutagenesis; nonhuman; priority journal; prolactin secreting cell; protein analysis; protein binding; protein expression; protein function; protein localization; protein protein interaction; rat; Animals; Binding Sites; Bone Morphogenetic Protein 4; Cells, Cultured; Estrogens; Lactotrophs; Prolactin; Promoter Regions, Genetic; Protein Binding; Rats; Receptor Cross-Talk; Receptors, Estrogen; Smad Proteins; Transcriptional Activation; Transforming Growth Factor beta
Página de inicio:1102
Página de fin:1114
Título revista:Molecular Endocrinology
Título revista abreviado:Mol. Endocrinol.
CAS:Smad protein, 62395-38-4; Smad1 protein, 444952-89-0; fulvestrant, 129453-61-8; prolactin, 12585-34-1, 50647-00-2, 9002-62-4; Bmp4 protein, rat; Bone Morphogenetic Protein 4; Estrogens; Prolactin, 9002-62-4; Receptors, Estrogen; Smad Proteins; Transforming Growth Factor beta


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---------- APA ----------
Giacomini, D., Páez-Pereda, M., Stalla, J., Stalla, G.K. & Arzt, E. (2009) . Molecular interaction of BMP-4, TGF-β, and estrogens in lactotrophs: Impact on the PRL promoter. Molecular Endocrinology, 23(7), 1102-1114.
---------- CHICAGO ----------
Giacomini, D., Páez-Pereda, M., Stalla, J., Stalla, G.K., Arzt, E. "Molecular interaction of BMP-4, TGF-β, and estrogens in lactotrophs: Impact on the PRL promoter" . Molecular Endocrinology 23, no. 7 (2009) : 1102-1114.
---------- MLA ----------
Giacomini, D., Páez-Pereda, M., Stalla, J., Stalla, G.K., Arzt, E. "Molecular interaction of BMP-4, TGF-β, and estrogens in lactotrophs: Impact on the PRL promoter" . Molecular Endocrinology, vol. 23, no. 7, 2009, pp. 1102-1114.
---------- VANCOUVER ----------
Giacomini, D., Páez-Pereda, M., Stalla, J., Stalla, G.K., Arzt, E. Molecular interaction of BMP-4, TGF-β, and estrogens in lactotrophs: Impact on the PRL promoter. Mol. Endocrinol. 2009;23(7):1102-1114.