{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:23:11Z","timestamp":1790504591848,"version":"4.1.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2013,12,1]],"date-time":"2013-12-01T00:00:00Z","timestamp":1385856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Previous studies of pulmonary arterial hypertension (PAH) have implicated excessive transforming growth factor (TGF)-\u03b21 signaling and reduced bone morphogenetic protein (BMP) signaling in the disease pathogenesis. Reduced BMP signaling in pulmonary artery smooth muscle cells (PASMCs) from patients with heritable PAH is a consequence of germline mutations in the BMP type II receptor (BMPR-II). We sought to establish whether the TGF-\u03b21 and BMP4 pathways interact in PASMCs, and if this is altered in cells with BMPR-II mutations. Control PASMCs or from patients with PAH harboring BMPR-II mutations were treated with BMP4, TGF-\u03b21, or cotreated with both ligands. Signaling was assessed by examination of Smad phosphorylation, luciferase reporters, and the transcription of BMP4 or TGF-\u03b21\u2013responsive genes. TGF-\u03b21 attenuated BMP4-mediated inhibitors of differentiation 1\/2 induction and abolished the response in BMPR-II mutant PASMCs, whereas BMP4 did not alter TGF-\u03b21\u2013mediated transcription. Activin-like kinase 5 inhibition blocked this effect, whereas cycloheximide or pharmacological inhibitors of TGF-\u03b2\u2013activated kinase 1, extracellular signal\u2013regulated kinase 1\/2, or p38 mitogen-activated protein kinase were ineffective. BMP4 and TGF-\u03b21 cotreatment did not alter the activation or nuclear translocation of their respective Smad signaling proteins. Small interfering RNA for Smad3, but not Smad2, Smad6, or Smad7, reversed the inhibition by TGF-\u03b21. In addition, TGF-\u03b2\u2013activated kinase 1 inhibition blocked Smad3 phosphorylation, implying that C-terminal Smad3 phosphorylation is not required for the inhibition of BMP4 signaling by TGF-\u03b21. TGF-\u03b21 reduces BMP4 signaling in PASMCs, a response that is exacerbated on the background of reduced BMP responsiveness due to BMPR-II mutations. These data provide a rationale for therapeutic inhibition of TGF-\u03b21 signaling in PAH.<\/jats:p>","DOI":"10.1165\/rcmb.2012-0470oc","type":"journal-article","created":{"date-parts":[[2013,8,12]],"date-time":"2013-08-12T15:43:25Z","timestamp":1376322205000},"page":"1135-1145","source":"Crossref","is-referenced-by-count":59,"title":["Transforming Growth Factor-\u03b21 Represses Bone Morphogenetic Protein\u2013Mediated Smad Signaling in Pulmonary Artery Smooth Muscle Cells via Smad3"],"prefix":"10.1093","volume":"49","author":[{"given":"Paul D.","family":"Upton","sequence":"first","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel J.","family":"Davies","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Tajsic","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,12,1]]},"reference":[{"key":"2026021904240163700_bib1","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s10555-012-9375-7","article-title":"TGF-beta signalling and its role in cancer progression and metastasis","volume":"31","author":"Drabsch","year":"2012","journal-title":"Cancer Metastasis Rev"},{"key":"2026021904240163700_bib2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1177\/1753465810379801","article-title":"The pathogenesis of idiopathic pulmonary fibrosis","volume":"4","author":"Coward","year":"2010","journal-title":"Ther Adv Respir Dis"},{"key":"2026021904240163700_bib3","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00441-011-1275-6","article-title":"Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects","volume":"347","author":"Lopez-Hernandez","year":"2012","journal-title":"Cell Tissue Res"},{"key":"2026021904240163700_bib4","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1161\/CIRCULATIONAHA.108.821504","article-title":"Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor\u2013like kinase-5 inhibition in prevention and progression of disease","volume":"119","author":"Long","year":"2009","journal-title":"Circulation"},{"key":"2026021904240163700_bib5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.2353\/ajpath.2009.080565","article-title":"Activin-like kinase 5 (ALK5) mediates abnormal proliferation of vascular smooth muscle cells from patients with familial pulmonary arterial hypertension and is involved in the progression of experimental pulmonary arterial hypertension induced by monocrotaline","volume":"174","author":"Thomas","year":"2009","journal-title":"Am J Pathol"},{"key":"2026021904240163700_bib6","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1164\/rccm.200707-1083OC","article-title":"Role of the TGF-\u03b2\/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension","volume":"177","author":"Zaiman","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904240163700_bib7","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1016\/j.jacc.2009.04.015","article-title":"Genetics and genomics of pulmonary arterial hypertension","volume":"54","author":"Machado","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2026021904240163700_bib8","doi-asserted-by":"crossref","first-page":"585S","DOI":"10.1378\/chest.128.6_suppl.585S","article-title":"Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders","volume":"128","author":"Bertolino","year":"2005","journal-title":"Chest"},{"key":"2026021904240163700_bib9","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.1074\/jbc.M111023200","article-title":"Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter","volume":"277","author":"Korchynskyi","year":"2002","journal-title":"J Biol Chem"},{"key":"2026021904240163700_bib10","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/39348","article-title":"Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1","volume":"389","author":"Kretzschmar","year":"1997","journal-title":"Nature"},{"key":"2026021904240163700_bib11","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.molcel.2007.01.006","article-title":"Balancing BMP signaling through integrated inputs into the Smad1 linker","volume":"25","author":"Sapkota","year":"2007","journal-title":"Mol Cell"},{"key":"2026021904240163700_bib12","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1161\/CIRCRESAHA.109.209940","article-title":"Smad-dependent and Smad-independent induction of Id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo","volume":"107","author":"Yang","year":"2010","journal-title":"Circ Res"},{"key":"2026021904240163700_bib13","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.cell.2009.09.035","article-title":"Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways","volume":"139","author":"Alarcon","year":"2009","journal-title":"Cell"},{"key":"2026021904240163700_bib14","doi-asserted-by":"crossref","first-page":"40412","DOI":"10.1074\/jbc.M610172200","article-title":"Dephosphorylation of the linker regions of Smad1 and Smad2\/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways","volume":"281","author":"Sapkota","year":"2006","journal-title":"J Biol Chem"},{"key":"2026021904240163700_bib15","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1210\/me.2010-0305","article-title":"Suppression of BMP-Smad signaling axis\u2013induced osteoblastic differentiation by small C-terminal domain phosphatase 1, a Smad phosphatase","volume":"25","author":"Kokabu","year":"2011","journal-title":"Mol Endocrinol"},{"key":"2026021904240163700_bib16","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1359\/jbmr.090736","article-title":"Protein phosphatase magnesium\u2013dependent 1A-mediated inhibition of BMP signaling is independent of Smad dephosphorylation","volume":"25","author":"Kokabu","year":"2010","journal-title":"J Bone Miner Res"},{"key":"2026021904240163700_bib17","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.cell.2006.03.044","article-title":"PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling","volume":"125","author":"Lin","year":"2006","journal-title":"Cell"},{"key":"2026021904240163700_bib18","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1161\/01.RES.0000166926.54293.68","article-title":"Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension","volume":"96","author":"Yang","year":"2005","journal-title":"Circ Res"},{"key":"2026021904240163700_bib19","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1161\/CIRCRESAHA.108.173567","article-title":"Mutations in bone morphogenetic protein type II receptor cause dysregulation of Id gene expression in pulmonary artery smooth muscle cells: implications for familial pulmonary arterial hypertension","volume":"102","author":"Yang","year":"2008","journal-title":"Circ Res"},{"key":"2026021904240163700_bib20","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1161\/hc3201.094152","article-title":"Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins","volume":"104","author":"Morrell","year":"2001","journal-title":"Circulation"},{"key":"2026021904240163700_bib21","doi-asserted-by":"crossref","first-page":"L604","DOI":"10.1152\/ajplung.00309.2011","article-title":"BMP type II receptor deficiency confers resistance to growth inhibition by TGF-beta in pulmonary artery smooth muscle cells: role of proinflammatory cytokines","volume":"302","author":"Davies","year":"2012","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904240163700_bib22","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1161\/ATVBAHA.107.141200","article-title":"Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension","volume":"27","author":"Morty","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026021904240163700_bib23","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/jbmr.313","article-title":"Biphasic effects of transforming growth factor beta on bone morphogenetic protein\u2013induced osteoblast differentiation","volume":"26","author":"de Gorter","year":"2011","journal-title":"J Bone Miner Res"},{"key":"2026021904240163700_bib24","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.2106\/00004623-200308000-00017","article-title":"Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs)","volume":"85-A","author":"Cheng","year":"2003","journal-title":"J Bone Joint Surg Am"},{"key":"2026021904240163700_bib25","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1128\/MCB.00231-12","article-title":"Transforming growth factor beta inhibits bone morphogenetic protein\u2013induced transcription through novel phosphorylated Smad1\/5-Smad3 complexes","volume":"32","author":"Gronroos","year":"2012","journal-title":"Mol Cell Biol"},{"key":"2026021904240163700_bib26","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/sj.emboj.7600067","article-title":"Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells","volume":"23","author":"Maeda","year":"2004","journal-title":"EMBO J"},{"key":"2026021904240163700_bib27","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1242\/dev.01930","article-title":"C-terminal mutants of C. elegans Smads reveal tissue-specific requirements for protein activation by TGF-beta signaling","volume":"132","author":"Wang","year":"2005","journal-title":"Development"},{"key":"2026021904240163700_bib28","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1161\/01.CIR.0000012754.72951.3D","article-title":"Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor","volume":"105","author":"Atkinson","year":"2002","journal-title":"Circulation"},{"key":"2026021904240163700_bib29","doi-asserted-by":"crossref","first-page":"L120","DOI":"10.1152\/ajplung.00171.2005","article-title":"BMP-7 opposes TGF-beta1\u2013mediated collagen induction in mouse pulmonary myofibroblasts through Id2","volume":"290","author":"Izumi","year":"2006","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904240163700_bib30","doi-asserted-by":"crossref","first-page":"8094","DOI":"10.1074\/jbc.M413102200","article-title":"Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney","volume":"280","author":"Zeisberg","year":"2005","journal-title":"J Biol Chem"},{"key":"2026021904240163700_bib31","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1465-9921-11-85","article-title":"Bone morphogenetic protein (BMP)-4 and BMP-7 regulate differentially transforming growth factor (TGF)-beta1 in normal human lung fibroblasts (NHLF)","volume":"11","author":"Pegorier","year":"2010","journal-title":"Respir Res"},{"key":"2026021904240163700_bib32","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/cr.2008.321","article-title":"Smad3 mediates immediate early induction of Id1 by TGF-beta","volume":"19","author":"Liang","year":"2009","journal-title":"Cell Res"},{"key":"2026021904240163700_bib33","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/S1097-2765(03)00109-6","article-title":"A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells","volume":"11","author":"Kang","year":"2003","journal-title":"Mol Cell"},{"key":"2026021904240163700_bib34","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1101\/gad.925901","article-title":"TGF-beta inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3","volume":"15","author":"Liu","year":"2001","journal-title":"Genes Dev"},{"key":"2026021904240163700_bib35","doi-asserted-by":"crossref","first-page":"13637","DOI":"10.1074\/jbc.274.19.13637","article-title":"Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells","volume":"274","author":"Ishisaki","year":"1999","journal-title":"J Biol Chem"},{"key":"2026021904240163700_bib36","doi-asserted-by":"crossref","first-page":"29195","DOI":"10.1074\/jbc.273.44.29195","article-title":"Transforming growth factor beta1 induces nuclear export of inhibitory Smad7","volume":"273","author":"Itoh","year":"1998","journal-title":"J Biol Chem"},{"key":"2026021904240163700_bib37","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1093\/emboj\/21.7.1743","article-title":"Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors","volume":"21","author":"Goumans","year":"2002","journal-title":"EMBO J"},{"key":"2026021904240163700_bib38","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1093\/emboj\/17.11.3091","article-title":"Direct binding of Smad3 and Smad4 to critical TGF beta\u2013inducible elements in the promoter of human plasminogen activator inhibitor\u2013type 1 gene","volume":"17","author":"Dennler","year":"1998","journal-title":"EMBO J"},{"key":"2026021904240163700_bib39","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/sj.onc.1209826","article-title":"Smad3 is acetylated by p300\/CBP to regulate its transactivation activity","volume":"26","author":"Inoue","year":"2007","journal-title":"Oncogene"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/49\/6\/1135\/66894811\/ajrcmb_49_6_1135.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/49\/6\/1135\/66894811\/ajrcmb_49_6_1135.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:26:25Z","timestamp":1771493185000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/49\/6\/1135\/8483192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,1]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2013,12,1]]},"published-print":{"date-parts":[[2013,12,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2012-0470oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,12]]},"published":{"date-parts":[[2013,12,1]]}}}