MicroRNA-155 controls RB phosphorylation in normal and malignant B lymphocytes via the noncanonical TGF-β1/SMAD5 signaling module

Blood. 2014 Jan 2;123(1):86-93. doi: 10.1182/blood-2013-07-515254. Epub 2013 Oct 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Cell Cycle
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Phosphorylation
  • Retinoblastoma Protein / metabolism*
  • Signal Transduction
  • Smad5 Protein / metabolism*
  • Spleen / metabolism
  • T-Lymphocytes / immunology
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • MicroRNAs
  • Mirn155 microRNA, mouse
  • Retinoblastoma Protein
  • Smad5 Protein
  • Smad5 protein, mouse
  • Transforming Growth Factor beta1