The TGF-β1–pRB axis in distinct miR-155 contexts. Outcome of the TGF-β1 activation of SMAD5 in DLBCL (A), which often expresses high levels of miR-155. In these malignant cells, miR-155 will markedly suppress SMAD5 expression, resulting in defective p15/p21 transcriptional induction and limited inhibition of the cyclin-dependent kinase (CDK)–cyclin complex–mediated phosphorylation of RB. The resulting hyperphosphorylated (inactive) RB allows tumor cells to progress through the cell cycle irrespective of prohibitive extracellular TGF-β signals instructing G0/G1 arrest. Mature B cells lacking miR-155 (B). In this instance, elevated SMAD5 expression sensitizes the cells to TGF-β1–mediated induction of p15/p21. The high expression of these CDK inhibitors blocks the CDK–cyclin complex and the hypophosphorylated (active) RB promotes cell-cycle arrest. This scenario may explain the defective germinal center B-cell development found in miR-155 null mice. In this diagram, stimulatory interactions are indicated with →; inhibitory interactions with ⊥. Professional illustration by Marie Dauenheimer.