title: MicroRNA-155 controls RB phosphorylation in normal and malignant B lymphocytes via the noncanonical TGF-β1/SMAD5 signaling module.
abstract: MicroRNA-155 (miR-155) plays pleiotropic roles in the biology of normal and malignant B lymphocytes, including the modulation of the transforming growth factor β (TGF-β) pathway via the targeting of SMAD5. However, the extent of the miR-155-mediated disruption of the TGF-β1/SMAD5 axis remains to be elucidated. To address this issue, we used the miR-155 knockout (KO) mouse and diffuse large B-cell lymphoma (DLBCL) cell lines ectopically expressing miR-155. In the DLBCL models, expression of miR-155 blocked TGF-β1-mediated activation of the retinoblastoma protein (RB), decreasing the abundance of the inhibitory pRB-E2F1 complex and limiting G0/G1 arrest. Genetic knockdown of SMAD5, p15, or p21 recapitulated these effects, establishing a circuitry whereby the targeting of SMAD5 by miR-155 blunts the TGF-β1-induced transcription of p15 and p21, thus sustaining RB phosphorylation and inactivity. Next, we demonstrated that SMAD5 levels are elevated in mature B lymphocytes from the miR-155 KO mice, which display a heightened sensitivity to TGF-β1 characterized by suppression of RB phosphorylation and more pronounced G0/G1 cell cycle arrest. Our findings suggest that a miR-155-mediated perturbation of the RB/E2F axis may play a role in DLBCL pathogenesis, and contribute to the reduced number of germinal center B cells and impaired T cell-dependent antibody response found in the miR-155 KO mice.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine.
authors.forename: Daifeng
authors.initials: D
authors.lastname: Jiang
authors.forename: Ricardo C T
authors.initials: RC
authors.lastname: Aguiar
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D051902:Smad5 Protein / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016160:Retinoblastoma Protein; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D053773:Transforming Growth Factor beta1