Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk

Pituitary tumor development involves clonal expansion stimulated by hormones and growth factors/cytokines. Using mRNA differential display, we found that the bone morphogenetic protein (BMP inhibitor noggin is down-regulated in prolactinomas from dopamine D2-receptor-deficient mice. BMP-4 is overexp...

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Autores principales: Páez Pereda, Marcelo, Giacomini, Damiana, Refojo, Damian, Carbia Nagashima, Alberto, Hopfner, Ursula, Grübler, Yvonne, Chervin, Alberto, Goldberg, Victoria, Goya, Rodolfo Gustavo, Hentges, Shane T., Low, Malcolm J., Holsboer, Florian, Stalla, Günter K., Arzt, Eduardo
Formato: Articulo
Lenguaje:Inglés
Publicado: 2003
Materias:
Ciencias Médicas
Ciencias Exactas
Pituitary neoplasms
Signal transduction
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/84588
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-84588
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Médicas
Ciencias Exactas
Pituitary neoplasms
Signal transduction
spellingShingle Ciencias Médicas
Ciencias Exactas
Pituitary neoplasms
Signal transduction
Páez Pereda, Marcelo
Giacomini, Damiana
Refojo, Damian
Carbia Nagashima, Alberto
Hopfner, Ursula
Grübler, Yvonne
Chervin, Alberto
Goldberg, Victoria
Goya, Rodolfo Gustavo
Hentges, Shane T.
Low, Malcolm J.
Holsboer, Florian
Stalla, Günter K.
Arzt, Eduardo
Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk
topic_facet Ciencias Médicas
Ciencias Exactas
Pituitary neoplasms
Signal transduction
description Pituitary tumor development involves clonal expansion stimulated by hormones and growth factors/cytokines. Using mRNA differential display, we found that the bone morphogenetic protein (BMP inhibitor noggin is down-regulated in prolactinomas from dopamine D2-receptor-deficient mice. BMP-4 is overexpressed in prolactinomas taken from dopamine D2-receptor-deficient female mice, but expression of the highly homologous BMP-2 does not differ in normal pituitary tissue and prolactinomas. BMP-4 is overexpressed in other prolactinoma models, including estradiol-induced rat prolactinomas and human prolactinomas, compared with normal tissue and other pituitary adenoma types (Western blot analysis of 48 tumors). BMP-4 stimulates, and noggin blocks, cell proliferation and the expression of c-Myc in human prolactinomas, whereas BMP-4 has no action in other human pituitary tumors. GH3 cells stably transfected with a dominant negative of Smad4 (Smad4dn; a BMP signal cotransducer) or noggin have reduced tumorigenicity in nude mice. Tumor growth recovered <i>in vivo</i> when the Smad4dn expression was lost, proving that BMP-4/Smad4 are involved in tumor development <i>in vivo</i>. BMP-4 and estrogens act through overlapping intracellular signaling mechanisms on GH3 cell proliferation and c-myc expression: they had additive effects at low concentrations but not at saturating doses, and their action was inhibited by blocking either pathway with the reciprocal antagonist (i.e., BMP-4 with ICI 182780 or 17β-estradiol with Smad4dn). Furthermore, coimmunoprecipitation studies demonstrate that under BMP-4 stimulation Smad4 and Smadl physically interact with the estrogen receptor. This previously undescribed prolactinoma pathogenesis mechanism may participate in tumorigenicity in other cells where estrogens and the type β transforming growth factor family have important roles.
format Articulo
Articulo
author Páez Pereda, Marcelo
Giacomini, Damiana
Refojo, Damian
Carbia Nagashima, Alberto
Hopfner, Ursula
Grübler, Yvonne
Chervin, Alberto
Goldberg, Victoria
Goya, Rodolfo Gustavo
Hentges, Shane T.
Low, Malcolm J.
Holsboer, Florian
Stalla, Günter K.
Arzt, Eduardo
author_facet Páez Pereda, Marcelo
Giacomini, Damiana
Refojo, Damian
Carbia Nagashima, Alberto
Hopfner, Ursula
Grübler, Yvonne
Chervin, Alberto
Goldberg, Victoria
Goya, Rodolfo Gustavo
Hentges, Shane T.
Low, Malcolm J.
Holsboer, Florian
Stalla, Günter K.
Arzt, Eduardo
author_sort Páez Pereda, Marcelo
title Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk
title_short Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk
title_full Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk
title_fullStr Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk
title_full_unstemmed Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk
title_sort involvement of bone morphogenetic protein 4 (bmp-4) in pituitary prolactinoma pathogenesis through a smad/estrogen receptor crosstalk
publishDate 2003
url http://sedici.unlp.edu.ar/handle/10915/84588
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