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

Páez-Pereda, Marcelo; Giacomini, Damiana; Refojo, Damián; Nagashima, Alberto Carbia; Hopfner, Úrsula; Grübler, Yvonne; Chervin, Alberto; Goldberg, Victoria; Goya, Rodolfo G.; Hentges, Shane T.; Low, Malcolm J.; Holsboer, Florian; Stalla, Günter; Arzt, Eduardo

doi:10.1073/pnas.0237312100

Cited by 167 publications

(171 citation statements)

References 57 publications

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“…In the current study, the interaction of Smads with ERa resulted in the blockade of activin signaling by estrogen. In accordance, previous studies demonstrated that estrogen signaling repressed transcription of TGF-b and bone morphogenetic protein (BMP) signals (Matsuda et al 2001, Yamamoto et al 2002, Paez-Pereda et al 2003, Helms et al 2005. Smads and ERa formed complexes in previous studies that could be co-immunoprecipitated (Hayes et al 2001, Matsuda et al 2001, Yamamoto et al 2002, Wu et al 2003.…”

Section: Discussionsupporting

confidence: 69%

Activin and estrogen crosstalk regulates transcription in human breast cancer cells

Burdette

Woodruff²

2007

Endocr Relat Cancer

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Activin is a member of the transforming growth factor b superfamily that regulates mammary cell function during development, lactation, and in cancer. Activin slows the growth of breast cancer cells by inducing G 0 /G 1 cell cycle arrest. Estrogen is a steroid hormone that stimulates the proliferation of mammary epithelial cells in development and oncogenesis. The crosstalk between estrogen and activin that regulates activin ligand expression, activin and estrogen signal transduction, and cell cycle arrest was investigated in this study. Estrogen antagonized activindependent production of plasminogen activator inhibitor 1 (PAI-1) mRNA, while activin repressed estrogen-dependent transcription of trefoil factor 1. The repression of estrogen signaling by activin was recapitulated using a simple estrogen response element-luciferase construct and was enhanced in the presence of overexpressed estrogen receptor a (ERa). In contrast, estrogenmediated repression of activin signaling could not be recapitulated on a simple CAGA Smadbinding element but did inhibit the short PAI-1 promoter, p3TP-luciferase, especially when ERa was overexpressed. Repression of both estrogen-and activin-regulated transcription was found to be ligand induced and Smad3 dependent. In addition to transcriptional repression, estrogen also reduced the amount of activin B mRNA and protein produced by MCF7 breast cancer cells. These studies demonstrate the importance of activin and estrogen crosstalk during mammary cell growth and cancer initiation.

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Section: Discussionsupporting

confidence: 69%

Activin and estrogen crosstalk regulates transcription in human breast cancer cells

Burdette

Woodruff²

2007

Endocr Relat Cancer

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“…Animals were examined for tumour formation periodically, and tumour growth was determined as described (22,29,30). The experiments were stopped at 50 days after cell injection, when animals were killed and the tumours were extracted and immediately frozen for inmunohistochemical staining.…”

Section: In Vivo Experiments In Nude Micementioning

confidence: 99%

Involvement of the gp130 cytokine transducer in MtT/S pituitary somatotroph tumour development in an autocrine-paracrine model

Graciarena

Carbia-Nagashima²,

Onofri

et al. 2004

European Journal of Endocrinology

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Objective: gp130 cytokines are placed as auto-paracrine regulators of pituitary function, since they, as well as their receptors, have been shown to be expressed in and to act in normal and tumoral anterior pituitary cells. The objective of this work was to study their involvement in a model that shows the interaction between different cellular types that participate in a tumorigenic process. Design: The dependence of a pituitary somatotrophic cell line (MtT/S) on a gp130 cytokine-producing folliculostellate (FS) cell line (TtT/GF) for tumorigenesis in vivo has been described. In order to study the participation of gp130 cytokines in the auto-paracrine stimulation of MtT/S growth, we generated MtT/S gp130 sense (gp130-S) and gp130 antisense (gp130-AS) clones stably transfected with pcDNA3/gp130 sense and pcDNA3/gp130 antisense vectors respectively. Methods and results: Functional characterization studies revealed that gp130-AS clones have an inhibited gp130 signalling, and proliferation studies showed that they have an impaired response to gp130 cytokines but respond normally to other independent stimuli. When injected into nude mice, MtT/S clones respond differently depending on cell number; at high concentrations MtT/S clones alone generated tumours equivalent in size to tumours derived from MtT/S plus TtT/GF cells. At low concentrations, MtT/S sense and control clones generated tumours of smaller size than tumours derived from these same clones plus TtT/GF cells, showing a dependence on FS cells. In both cases MtT/S gp130-AS clones had impaired tumour development. Furthermore, vessel density was significantly lower in tumours derived from gp130-AS plus TtT/GF cells. Conclusions: This study underlines the importance of gp130 cytokines in proliferation and establishes its role in auto-paracrine pituitary growth regulation.European Journal of Endocrinology 151 595-604

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“…BMP-4 not only governs this pituitary organogenesis but also plays a key role in the pathogenesis of differentiated pituitary lineages. For instance, BMP-4 is overexpressed in lactotrope adenomas derived from D2R-null mice as well as human prolactinomas (Paez-Pereda et al 2003). A binding protein for BMPs, noggin expression is conversely downregulated in the prolactinoma from the D2R-null mouse (Paez-Pereda et al 2003), suggesting that BMP-4 promotes cell proliferation in lactotropes in conjunction with Smad-estrogen receptor interaction under the influence of its binding protein.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that locally produced BMPs play key roles in differentiation of the pituitary. For instance, BMP-4 promotes pituitary prolactinoma pathogenesis through crosstalk between the BMP-4-mediated Smads and the estrogen receptor (Paez-Pereda et al 2003). BMP-4 also inhibits corticotropic pathogenesis and Cushing's disease in adult pituitary tumor cells (Giacomini et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells

Miyoshi¹,

Otsuka²,

Otani³

et al. 2008

Journal of Endocrinology

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Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6; BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolininduced GH secretion. A low concentration (0 . 1 mM) of OCT in combination with BRC (1-100 mM) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 mM) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP-4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.

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

Cited by 167 publications

References 57 publications

Activin and estrogen crosstalk regulates transcription in human breast cancer cells

Activin and estrogen crosstalk regulates transcription in human breast cancer cells

Involvement of the gp130 cytokine transducer in MtT/S pituitary somatotroph tumour development in an autocrine-paracrine model

Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells

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