Evidence is also accumulating for novel mechanisms by which miRNAs can directly regulate mRNAs by facilitating or preventing interaction with RNA-binding proteins. An example of this that also underscores the fact that mRNA stability can be affected by environmental factors, is miR-369-3p (one of the upregulated miRNAs in human alcoholics), which associates directly with the AU-rich elements (AREs) in TNFα mRNA by base pairing and mediates translational activation of TNFα only under growth arrest conditions (Vasudevan and Steitz, 2007; Vasudevan et al., 2007). This effect was dependent on the recruitment of the RNA-binding proteins fragile-X mental retardation-related protein 1 (FXR1) and argonaute 2 (AGo2) and could be reversed when cells were actively proliferating, in which case miR-369-3p would switch roles to represses TNFα. Discovery of such sensitive and complex switch-like regulatory mechanisms emphasizes the extreme fine-tuning capabilities encoded into the biology of miRNAs.
