IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
artículos
Título:
Molecular interaction of BMP-4, TGF-beta, and estrogens in lactotrophs: impact on the PRL promoter
Autor/es:
GIACOMINI D; PAEZ PEREDA M; STALLA J; STALLA GK; ARZT E
Revista:
MOLECULAR ENDOCRINOLOGY
Referencias:
Año: 2009 vol. 23 p. 1102 - 1114
ISSN:
0888-8809
Resumen:
The regulatory role of estrogen, bone morphogenetic protein-4 (BMP-4),
and TGF-beta has a strong impact on hormone secretion, gene
transcription, and cellular growth of prolactin (PRL)-producing cells.
In contrast to TGF-beta, BMP-4 induces the secretion of PRL in GH3
cells. Therefore, we studied the mechanism of their transcriptional
regulation. Both BMP-4 and TGF-beta inhibited the transcriptional
activity of the estrogen receptor (ER). Estrogens had no effect on
TGF-beta-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-beta, and estrogens in PRL-producing cells.