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

dc.creatorPáez Pereda, Marcelo
dc.creatorGiacomini, Damiana
dc.creatorRefojo, Damian
dc.creatorCarbia Nagashima, Alberto
dc.creatorHopfner, Ursula
dc.creatorGrübler, Yvonne
dc.creatorChervin, Alberto
dc.creatorGoldberg, Victoria
dc.creatorGoya, Rodolfo Gustavo
dc.creatorHentges, Shane T.
dc.creatorLow, Malcolm J.
dc.creatorHolsboer, Florian
dc.creatorStalla, Günter K.
dc.creatorArzt, Eduardo
dc.date2003
dc.date2019-10-31T18:09:22Z
dc.identifierhttp://sedici.unlp.edu.ar/handle/10915/84588
dc.identifierissn:0027-8424
dc.descriptionPituitary 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.
dc.descriptionFacultad de Ciencias Exactas
dc.descriptionInstituto de Investigaciones Bioquímicas de La Plata
dc.formatapplication/pdf
dc.format1034-1039
dc.languageen
dc.rightshttp://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rightsCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
dc.subjectCiencias Médicas
dc.subjectCiencias Exactas
dc.subjectPituitary neoplasms
dc.subjectSignal transduction
dc.titleInvolvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk
dc.typeArticulo
dc.typeArticulo


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