TGFbeta-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation.
We have previously reported an overexpression of Smad1 in follicular lymphoma (FL) cells, which are characterized by the t(14;18) bcl2/IgH translocation. Smad1 is commonly involved in bone morphogenetic protein but not in tumor-transforming growth factor beta (TGFbeta) signaling pathways. This study focuses on Smad1 signaling pathway in non-Hodgkin lymphoma cells including follicular or large-cell lymphoma cells. Our results support the notion that phosphorylation of Smad1 is mediated by TGFbeta present in the microenvironment and occurs in FL in vivo. Using an in vitro coculture system mimicking interactions between stroma cells and FL cells, we found that both the cell partners release TGFbeta at a sufficient concentration to activate Smad pathways in the malignant cells. This Smad1 activation involves TGFbetaRII but not ALK-1 receptors, and does not compete with the Smad2 pathway. Moreover, proliferation assays performed on lymphoma cells expressing wild-type or mutated Smad1, or in which endogenous Smad1 level was decreased by gene silencing, strongly supported that overexpression and activation of Smad1 modifies the biological response of lymphoma B cells to TGFbeta family members. This work opens new insights into aberrant Smad pathways and their pathophysiological role in FL and in other non-Hodgkin lymphomas.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. omunoz@partners.org
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Munoz
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Fend
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de Beaumont
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Husson
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Astier
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Freedman
D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II; D001402:B-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000378:metabolism* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D014066:Palatine Tonsil / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins; D051898:Smad1 Protein; D051899:Smad2 Protein; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497399:SMAD1 protein, human; C497782:SMAD2 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D000077294:Receptor, Transforming Growth Factor-beta Type II