Molecular interaction of BMP-4, TGF-β, and estrogens in lactotrophs: Impact on the PRL promoter

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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 mech...

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Detalles Bibliográficos
Autores principales: Giacomini, D., Páez-Pereda, M., Stalla, J., Stalla, G.K., Arzt, E.
Formato: JOUR
Materias:
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
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_08888809_v23_n7_p1102_Giacomini
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario: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.

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