MicroRNA-155 controls RB phosphorylation in normal and malignant B lymphocytes via the non-canonical TGFβ1-SMAD5 signaling module

Daifeng Jiang, Ricardo C.T. Aguiar

Key points

  • MicroRNA-155 regulates the RB/E2F axis in DLBCL

  • SMAD5 plays a dominant role in transducing TGFβ effects towards B lymphocytes


MicroRNA-155 plays pleiotropic roles in the biology of normal and malignant B lymphocytes, including the modulation of the TGFβ pathway via the targeting of SMAD5. However, the extent of the microRNA-155-mediated disruption of the TGFβ1-SMAD5 axis remains to be elucidated. To address this issue, we used the microRNA-155 knockout (KO) mouse, and diffuse large B-cell lymphoma (DLBCL) cell lines ectopically expressing microRNA-155. In the DLBCL models, expression of miR-155 blocked TGFβ1-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 microRNA-155 blunts the TGFβ1-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 microRNA-155 KO mice, which display a heightened sensitivity to TGFβ1 characterized by suppression of RB phosphorylation and more pronounced G0/G1 cell cycle arrest. Our findings suggest that perturbation of the RB/E2F axis may contribute to the DLBCL pathogenesis, and could contribute to the reduced number of germinal center B cells and impaired T cell-dependent antibody response found in the microRNA-155 KO mice.

  • Submitted July 15, 2013.
  • Accepted October 13, 2013.