Targeting of SMAD5 links microRNA-155 to the TGF-β pathway and lymphomagenesis
- 16 February 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (7), 3111-3116
- https://doi.org/10.1073/pnas.0910667107
Abstract
The mechanisms by which microRNA dysfunction contributes to the pathogenesis of diffuse large B cell lymphoma (DLBCL) are not well established. The identification of the genes and pathways directly targeted by these small regulatory RNAs is a critical step to advance this field. Using unbiased genome-wide approaches in DLBCL, we discovered that the oncogenic microRNA-155 (miR-155) directly targets the bone morphogenetic protein (BMP)-responsive transcriptional factor SMAD5. Surprisingly, we found that in DLBCL a noncanonical signaling module linking TGF-beta1 signals to SMAD5 is also active. In agreement with these data, miR-155 overexpression rendered DLBCLs resistant to the growth-inhibitory effects of both TGF-beta1 and BMPs, via defective induction of p21 and impaired cell cycle arrest. In confirmatory experiments, RNAi-based SMAD5 knockdown recapitulated in vitro and in vivo the effects miR-155 overexpression. Furthermore, in primary DLBCLs, miR-155 overexpression inhibited SMAD5 expression and disrupted its activity, as defined by individual and global analyses of its transcriptional targets. Together, our data helped explain miR-155 function, highlighted a hitherto unappreciated role of SMAD5 in lymphoma biology, and defined a unique mechanism used by cancer cells to escape TGF-beta's growth-inhibitory effects.This publication has 27 references indexed in Scilit:
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- Foxp3-Dependent MicroRNA155 Confers Competitive Fitness to Regulatory T Cells by Targeting SOCS1 ProteinImmunity, 2009
- TGFβ-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFβ switchThe EMBO Journal, 2008
- Transforming Growth Factor β-Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent GrowthMolecular and Cellular Biology, 2008
- MicroRNA-155 Suppresses Activation-Induced Cytidine Deaminase-Mediated Myc-Igh TranslocationImmunity, 2008
- Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytesNature Immunology, 2008
- Coordinated expression of microRNA-155 and predicted target genes in diffuse large B-cell lymphomaCancer Genetics and Cytogenetics, 2008
- Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorderThe Journal of Experimental Medicine, 2008
- Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in MiceMolecular and Cellular Biology, 2008
- microRNA-155 Regulates the Generation of Immunoglobulin Class-Switched Plasma CellsImmunity, 2007