{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T21:44:17Z","timestamp":1791150257160,"version":"4.1.0"},"reference-count":55,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Activin A is a potent growth and differentiation factor involved in development, differentiation, and physiological functions of the endocrine pancreas; it increases insulin and pax4 gene expression in \u03b2-cells and can induce transdifferentiation of the exocrine acinar cell line AR42J into insulin-producing cells. We show here that Activin A decreases glucagon gene expression in the \u03b1-cell lines InR1G9 and \u03b1TC1 in a dose- and time-dependent manner and that the effect is blocked by Follistatin. This effect is also observed in adult human islets. Glucagon gene expression is inhibited at the transcriptional level by the Smad signaling pathway through the G3 DNA control element. Furthermore, Activin A decreases cell proliferation of InR1G9 and \u03b1TC1 cells as well as cyclin D2 and arx gene expression, whose protein product Arx has been shown to be critical for \u03b1-cell differentiation. Overexpression of Arx in Activin A-treated InR1G9 cells does not prevent the decrease in glucagon gene expression but corrects the inhibition of cell proliferation, indicating that Arx mediates the Activin A effects on the cell cycle. We conclude that Activin A has opposite effects on \u03b1-cells compared with \u03b2-cells, a finding that may have relevance during pancreatic endocrine lineage specification and physiological function of the adult islets.<\/jats:p>","DOI":"10.1210\/me.2005-0530","type":"journal-article","created":{"date-parts":[[2006,9,21]],"date-time":"2006-09-21T00:57:01Z","timestamp":1158800221000},"page":"259-273","source":"Crossref","is-referenced-by-count":19,"title":["Activin A Decreases glucagon and arx Gene Expression in \u03b1-Cell Lines"],"prefix":"10.1210","volume":"21","author":[{"given":"Aline","family":"Mamin","sequence":"first","affiliation":[{"name":"Diabetes Unit, Division of Endocrinology, Diabetes and Nutrition, University Hospital G, 1211 Geneva 14, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Philippe","sequence":"additional","affiliation":[{"name":"Diabetes Unit, Division of Endocrinology, Diabetes and Nutrition, University Hospital G, 1211 Geneva 14, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614023897400_R1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S0092-8674(00)00121-5","article-title":"TGF\u03b2 signaling in growth control, cancer, and heritable disorders.","volume":"103","author":"Massague","year":"2000","journal-title":"Cell"},{"key":"2020071614023897400_R2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3181\/00379727-215-44130","article-title":"Activins, inhibins, and follistatins: further thoughts on a growing family of regulators.","volume":"215","author":"Mather","year":"1997","journal-title":"Proc Soc Exp Biol Med"},{"key":"2020071614023897400_R3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0925-4773(94)00295-X","article-title":"mRNAs for activin receptors II and IIB are expressed in mouse oocytes and in the epiblast of pregastrula and gastrula stage mouse embryos.","volume":"49","author":"Manova","year":"1995","journal-title":"Mech Dev"},{"key":"2020071614023897400_R4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1507\/endocrj.42.63","article-title":"Expression of immunoreactive activin A in fetal rat pancreas.","volume":"42","author":"Furukawa","year":"1995","journal-title":"Endocr J"},{"key":"2020071614023897400_R5","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S1091-255X(00)80075-X","article-title":"Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: implications for lineage selection.","volume":"4","author":"Maldonado","year":"2000","journal-title":"J Gastrointest Surg"},{"key":"2020071614023897400_R6","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1101\/gad.14.15.1866","article-title":"Activin receptor patterning of foregut organogenesis.","volume":"14","author":"Kim","year":"2000","journal-title":"Genes Dev"},{"key":"2020071614023897400_R7","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1046\/j.1440-169x.2000.00542.x","article-title":"In vitro pancreas formation from Xenopus ectoderm treated with activin and retinoic acid.","volume":"42","author":"Moriya","year":"2000","journal-title":"Dev Growth Differ"},{"key":"2020071614023897400_R8","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1172\/JCI118591","article-title":"Betacellulin and activin A coordinately convert amylase-secreting pancreatic AR42J cells into insulin-secreting cells.","volume":"97","author":"Mashima","year":"1996","journal-title":"J Clin Invest"},{"key":"2020071614023897400_R9","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.1172\/JCI117922","article-title":"Conversion of amylase-secreting rat pancreatic AR42J cells to neuronlike cells by activin A.","volume":"95","author":"Ohnishi","year":"1995","journal-title":"J Clin Invest"},{"key":"2020071614023897400_R10","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.2337\/diabetes.50.2007.S10","article-title":"Changes in the expression of transcription factors in pancreatic AR42J cells during differentiation into insulin-producing cells.","volume":"50","author":"Zhang","year":"2001","journal-title":"Diabetes"},{"key":"2020071614023897400_R11","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0014-5793(00)01914-1","article-title":"Activin A increases Pax4 gene expression in pancreatic beta cell lines.","volume":"480","author":"Ueda","year":"2000","journal-title":"FEBS Lett"},{"key":"2020071614023897400_R12","first-page":"3892","article-title":"A role for activin A and betacellulin in human fetal pancreatic cell differentiation and growth.","volume":"85","author":"Demeterco","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614023897400_R13","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1111\/j.0001-5172.2004.00425.x","article-title":"Efficacy of the A-line AEP monitor as a tool for predicting successful insertion of a laryngeal mask during sevoflurane anesthesia.","volume":"48","author":"Alpiger","year":"2004","journal-title":"Acta Anaesthesiol Scand"},{"key":"2020071614023897400_R14","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S1096-7192(02)00126-9","article-title":"Human ARX gene: genomic characterization and expression.","volume":"77","author":"Ohira","year":"2002","journal-title":"Mol Genet Metab"},{"key":"2020071614023897400_R15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-4889(99)00022-1","article-title":"Impaired differentiation of endocrine and exocrine cells of the pancreas in transgenic mouse expressing the truncated type II activin receptor.","volume":"1450","author":"Shiozaki","year":"1999","journal-title":"Biochim Biophys Acta"},{"key":"2020071614023897400_R16","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1172\/JCI2769","article-title":"Hypoplasia of pancreatic islets in transgenic mice expressing activin receptor mutants.","volume":"102","author":"Yamaoka","year":"1998","journal-title":"J Clin Invest"},{"key":"2020071614023897400_R17","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/002215540405200210","article-title":"Localization of inhibins and activins in normal endocrine cells and endocrine tumors of the gut and pancreas: an immunohistochemical and in situ hybridization study.","volume":"52","author":"La Rosa","year":"2004","journal-title":"J Histochem Cytochem"},{"key":"2020071614023897400_R18","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1530\/eje.0.1450225","article-title":"Expression and secretion of activin A: possible physiological and clinical implications.","volume":"145","author":"Luisi","year":"2001","journal-title":"Eur J Endocrinol"},{"key":"2020071614023897400_R19","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/0014-5793(93)80549-A","article-title":"Expression of \u03b1, \u03b2A and \u03b2B subunits of inhibin or activin and follistatin in rat pancreatic islets.","volume":"319","author":"Ogawa","year":"1993","journal-title":"FEBS Lett"},{"key":"2020071614023897400_R20","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1210\/endo.133.2.8344202","article-title":"Existence of activin-A in A- and D-cells of rat pancreatic islet.","volume":"133","author":"Yasuda","year":"1993","journal-title":"Endocrinology"},{"key":"2020071614023897400_R21","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/BF03343713","article-title":"Activin A stimulates insulin secretion in cultured human pancreatic islets.","volume":"23","author":"Florio","year":"2000","journal-title":"J Endocrinol Invest"},{"key":"2020071614023897400_R22","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0006-291X(88)80845-3","article-title":"A novel action of activin A: stimulation of insulin secretion in rat pancreatic islets.","volume":"156","author":"Totsuka","year":"1988","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071614023897400_R23","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/0024-3205(93)90260-A","article-title":"Activin A: its effects on rat pancreatic islets and the mechanism of action involved.","volume":"53","author":"Verspohl","year":"1993","journal-title":"Life Sci"},{"key":"2020071614023897400_R24","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/BF02623498","article-title":"Isolation of glucagon-secreting cell lines by cloning insulinoma cells.","volume":"22","author":"Takaki","year":"1986","journal-title":"In Vitro Cell Dev Biol"},{"key":"2020071614023897400_R25","doi-asserted-by":"crossref","first-page":"406","DOI":"10.2337\/diab.39.4.406","article-title":"Proglucagon processing similar to normal islets in pancreatic \u03b1-like cell line derived from transgenic mouse tumor.","volume":"39","author":"Powers","year":"1990","journal-title":"Diabetes"},{"key":"2020071614023897400_R26","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1242\/dev.01870","article-title":"The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the \u03b1- and \u03b2-cell lineages in the mouse endocrine pancreas.","volume":"132","author":"Collombat","year":"2005","journal-title":"Development"},{"key":"2020071614023897400_R27","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1101\/gad.269003","article-title":"Opposing actions of Arx and Pax4 in endocrine pancreas development.","volume":"17","author":"Collombat","year":"2003","journal-title":"Genes Dev"},{"key":"2020071614023897400_R28","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1210\/en.2002-220089","article-title":"Up-regulation of the expression of activins in the pancreatic duct by reduction of the \u03b2-cell mass.","volume":"143","author":"Zhang","year":"2002","journal-title":"Endocrinology"},{"key":"2020071614023897400_R29","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1046\/j.1432-1327.2000.01080.x","article-title":"Transforming growth factor beta induction of insulin gene expression is mediated by pancreatic and duodenal homeobox gene-1 in rat insulinoma cells.","volume":"267","author":"Sayo","year":"2000","journal-title":"Eur J Biochem"},{"key":"2020071614023897400_R30","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1101\/gad.859401","article-title":"Intercellular signals regulating pancreas development and function.","volume":"15","author":"Kim","year":"2001","journal-title":"Genes Dev"},{"key":"2020071614023897400_R31","doi-asserted-by":"crossref","first-page":"4877","DOI":"10.1128\/MCB.8.11.4877","article-title":"\u03b1-Cell-specific expression of the glucagon gene is conferred to the glucagon promoter element by the interactions of DNA-binding proteins.","volume":"8","author":"Philippe","year":"1988","journal-title":"Mol Cell Biol"},{"key":"2020071614023897400_R32","doi-asserted-by":"crossref","first-page":"27989","DOI":"10.1074\/jbc.M003345200","article-title":"Heterodimeric Pbx-Prep1 homeodomain protein binding to the glucagon gene restricting transcription in a cell type-dependent manner.","volume":"275","author":"Herzig","year":"2000","journal-title":"J Biol Chem"},{"key":"2020071614023897400_R33","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1074\/jbc.274.7.4124","article-title":"Pax-6 and Cdx-2\/3 interact to activate glucagon gene expression on the G1 control element.","volume":"274","author":"Ritz-Laser","year":"1999","journal-title":"J Biol Chem"},{"key":"2020071614023897400_R34","doi-asserted-by":"crossref","first-page":"3039","DOI":"10.1074\/jbc.270.7.3039","article-title":"Islet-specific proteins interact with the insulin-response element of the glucagon gene.","volume":"270","author":"Philippe","year":"1995","journal-title":"J Biol Chem"},{"key":"2020071614023897400_R35","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-\u03b2 family signalling.","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature"},{"key":"2020071614023897400_R36","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1172\/JCI22098","article-title":"\u03b2 Cell replication is the primary mechanism for maintaining postnatal \u03b2 cell mass.","volume":"114","author":"Georgia","year":"2004","journal-title":"J Clin Invest"},{"key":"2020071614023897400_R37","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1101\/gad.14.6.627","article-title":"Controlling TGF-\u03b2 signaling.","volume":"14","author":"Massague","year":"2000","journal-title":"Genes Dev"},{"key":"2020071614023897400_R38","doi-asserted-by":"crossref","first-page":"6952","DOI":"10.1073\/pnas.92.15.6952","article-title":"Activin A inhibits Pax-6 expression and perturbs cell differentiation in the developing spinal cord in vitro.","volume":"92","author":"Pituello","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614023897400_R39","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1210\/me.2003-0442","article-title":"Activin regulation of the follicle-stimulating hormone \u03b2-subunit gene involves Smads and the TALE homeodomain proteins Pbx1 and Prep1.","volume":"18","author":"Bailey","year":"2004","journal-title":"Mol Endocrinol"},{"key":"2020071614023897400_R40","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1128\/MCB.14.3.2066","article-title":"D-type cyclin-dependent kinase activity in mammalian cells.","volume":"14","author":"Matsushime","year":"1994","journal-title":"Mol Cell Biol"},{"key":"2020071614023897400_R41","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.2337\/diabetes.54.9.2568","article-title":"Differentiation of human liver-derived, insulin-producing cells toward the \u03b2-cell phenotype.","volume":"54","author":"Zalzman","year":"2005","journal-title":"Diabetes"},{"key":"2020071614023897400_R42","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1006\/cbir.2002.0965","article-title":"Exogenous activin increases the proportion of insulin cells in the developing chick pancreas in culture.","volume":"26","author":"Penny","year":"2002","journal-title":"Cell Biol Int"},{"key":"2020071614023897400_R43","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.1242\/dev.01535","article-title":"GDF11 modulates NGN3+ islet progenitor cell number and promotes \u03b2-cell differentiation in pancreas development.","volume":"131","author":"Harmon","year":"2004","journal-title":"Development"},{"key":"2020071614023897400_R44","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1101\/gad.340305","article-title":"Control of liver cell fate decision by a gradient of TGF\u03b2 signaling modulated by Onecut transcription factors.","volume":"19","author":"Clotman","year":"2005","journal-title":"Genes Dev"},{"key":"2020071614023897400_R45","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1097\/01.TP.0000147344.73915.C8","article-title":"Assessment of a novel two-component enzyme preparation for human islet isolation and transplantation.","volume":"79","author":"Bucher","year":"2005","journal-title":"Transplantation"},{"key":"2020071614023897400_R46","doi-asserted-by":"crossref","first-page":"413","DOI":"10.2337\/diab.37.4.413","article-title":"Automated method for isolation of human pancreatic islets.","volume":"37","author":"Ricordi","year":"1988","journal-title":"Diabetes"},{"key":"2020071614023897400_R47","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1056\/NEJM200007273430401","article-title":"Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.","volume":"343","author":"Shapiro","year":"2000","journal-title":"N Engl J Med"},{"key":"2020071614023897400_R48","doi-asserted-by":"crossref","first-page":"15659","DOI":"10.1016\/S0021-9258(18)47777-0","article-title":"Glucagon gene 5\u2032-flanking sequences promote islet cell-specific gene transcription.","volume":"262","author":"Drucker","year":"1987","journal-title":"J Biol Chem"},{"key":"2020071614023897400_R49","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1074\/jbc.270.7.3046","article-title":"The upstream promoter element of the glucagon gene, G1, confers pancreatic \u03b1 cell-specific expression.","volume":"270","author":"Morel","year":"1995","journal-title":"J Biol Chem"},{"key":"2020071614023897400_R50","doi-asserted-by":"crossref","first-page":"29113","DOI":"10.1074\/jbc.271.46.29113","article-title":"Liver-specific enhancer of the glucokinase gene.","volume":"271","author":"Iynedjian","year":"1996","journal-title":"J Biol Chem"},{"key":"2020071614023897400_R51","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0022-1759(94)90390-5","article-title":"A rapid method for measuring apoptosis and dual-color immunofluorescence by single laser flow cytometry.","volume":"170","author":"Schmid","year":"1994","journal-title":"J Immunol Methods"},{"key":"2020071614023897400_R52","doi-asserted-by":"crossref","first-page":"9037","DOI":"10.1073\/pnas.85.23.9037","article-title":"\u03b2-Cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene.","volume":"85","author":"Efrat","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614023897400_R53","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0092-8674(88)90017-7","article-title":"The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer.","volume":"55","author":"Kumar","year":"1988","journal-title":"Cell"},{"key":"2020071614023897400_R54","doi-asserted-by":"crossref","first-page":"4221","DOI":"10.1002\/j.1460-2075.1988.tb03319.x","article-title":"Identification of a novel lymphoid specific octamer binding protein (OTF-2B) by proteolytic clipping bandshift assay (PCBA).","volume":"7","author":"Schreiber","year":"1988","journal-title":"EMBO J"},{"key":"2020071614023897400_R55","doi-asserted-by":"crossref","first-page":"7224","DOI":"10.1073\/pnas.88.16.7224","article-title":"Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element.","volume":"88","author":"Philippe","year":"1991","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/21\/1\/259\/8960613\/mend0259.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/21\/1\/259\/8960613\/mend0259.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T22:50:44Z","timestamp":1683586244000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mend\/article\/21\/1\/259\/2738589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,1,1]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2007,1,1]]}},"URL":"https:\/\/doi.org\/10.1210\/me.2005-0530","relation":{},"ISSN":["0888-8809","1944-9917"],"issn-type":[{"value":"0888-8809","type":"print"},{"value":"1944-9917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,1,1]]}}}