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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2003
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v100_n3_p1034_PaezPereda http://hdl.handle.net/20.500.12110/paper_00278424_v100_n3_p1034_PaezPereda |
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paper:paper_00278424_v100_n3_p1034_PaezPereda2023-06-08T14:54:19Z Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk Pituitary neoplasms Signal transduction bone morphogenetic protein 4 cytokine dopamine 2 receptor estradiol estrogen receptor fulvestrant growth factor hormone derivative messenger RNA noggin Smad protein Smad1 protein transforming growth factor beta unclassified drug animal cell animal experiment animal model article carcinogenicity cell proliferation controlled study down regulation female gene overexpression hypophysis adenoma hypophysis tumor mouse nonhuman nude mouse oncogene c myc pathogenesis priority journal prolactinoma protein protein interaction signal transduction tumor growth Western blotting Animals Blotting, Western Bone Morphogenetic Proteins Cell Division DNA-Binding Proteins Estrogens Female Gene Expression Profiling Heterozygote Humans Mice Mice, Nude Pituitary Neoplasms Plasmids Precipitin Tests Prolactinoma Proto-Oncogene Proteins c-myc Rats Rats, Sprague-Dawley Receptors, Dopamine D2 Receptors, Estrogen Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Smad4 Protein Time Factors Trans-Activators Transcription Factors Transfection Animalia Mus musculus 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 in vivo when the Smad4dn expression was lost, proving that BMP-4/Smad4 are involved in tumor development in vivo. 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. 2003 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v100_n3_p1034_PaezPereda http://hdl.handle.net/20.500.12110/paper_00278424_v100_n3_p1034_PaezPereda |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Pituitary neoplasms Signal transduction bone morphogenetic protein 4 cytokine dopamine 2 receptor estradiol estrogen receptor fulvestrant growth factor hormone derivative messenger RNA noggin Smad protein Smad1 protein transforming growth factor beta unclassified drug animal cell animal experiment animal model article carcinogenicity cell proliferation controlled study down regulation female gene overexpression hypophysis adenoma hypophysis tumor mouse nonhuman nude mouse oncogene c myc pathogenesis priority journal prolactinoma protein protein interaction signal transduction tumor growth Western blotting Animals Blotting, Western Bone Morphogenetic Proteins Cell Division DNA-Binding Proteins Estrogens Female Gene Expression Profiling Heterozygote Humans Mice Mice, Nude Pituitary Neoplasms Plasmids Precipitin Tests Prolactinoma Proto-Oncogene Proteins c-myc Rats Rats, Sprague-Dawley Receptors, Dopamine D2 Receptors, Estrogen Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Smad4 Protein Time Factors Trans-Activators Transcription Factors Transfection Animalia Mus musculus |
| spellingShingle |
Pituitary neoplasms Signal transduction bone morphogenetic protein 4 cytokine dopamine 2 receptor estradiol estrogen receptor fulvestrant growth factor hormone derivative messenger RNA noggin Smad protein Smad1 protein transforming growth factor beta unclassified drug animal cell animal experiment animal model article carcinogenicity cell proliferation controlled study down regulation female gene overexpression hypophysis adenoma hypophysis tumor mouse nonhuman nude mouse oncogene c myc pathogenesis priority journal prolactinoma protein protein interaction signal transduction tumor growth Western blotting Animals Blotting, Western Bone Morphogenetic Proteins Cell Division DNA-Binding Proteins Estrogens Female Gene Expression Profiling Heterozygote Humans Mice Mice, Nude Pituitary Neoplasms Plasmids Precipitin Tests Prolactinoma Proto-Oncogene Proteins c-myc Rats Rats, Sprague-Dawley Receptors, Dopamine D2 Receptors, Estrogen Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Smad4 Protein Time Factors Trans-Activators Transcription Factors Transfection Animalia Mus musculus Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk |
| topic_facet |
Pituitary neoplasms Signal transduction bone morphogenetic protein 4 cytokine dopamine 2 receptor estradiol estrogen receptor fulvestrant growth factor hormone derivative messenger RNA noggin Smad protein Smad1 protein transforming growth factor beta unclassified drug animal cell animal experiment animal model article carcinogenicity cell proliferation controlled study down regulation female gene overexpression hypophysis adenoma hypophysis tumor mouse nonhuman nude mouse oncogene c myc pathogenesis priority journal prolactinoma protein protein interaction signal transduction tumor growth Western blotting Animals Blotting, Western Bone Morphogenetic Proteins Cell Division DNA-Binding Proteins Estrogens Female Gene Expression Profiling Heterozygote Humans Mice Mice, Nude Pituitary Neoplasms Plasmids Precipitin Tests Prolactinoma Proto-Oncogene Proteins c-myc Rats Rats, Sprague-Dawley Receptors, Dopamine D2 Receptors, Estrogen Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Smad4 Protein Time Factors Trans-Activators Transcription Factors Transfection Animalia Mus musculus |
| 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 in vivo when the Smad4dn expression was lost, proving that BMP-4/Smad4 are involved in tumor development in vivo. 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. |
| 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 |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v100_n3_p1034_PaezPereda http://hdl.handle.net/20.500.12110/paper_00278424_v100_n3_p1034_PaezPereda |
| _version_ |
1768544810039246848 |