Fig. 4.
miRNAs regulate factors that are important for cellular senescence. Numerous miRNAs regulate gene expression of components of aging pathways (outlined in separate boxes) on the cellular level. Stress-induced cellular senescence can be regulated by the MAPK pathway and interleukins, among other factors. Regarding MAPK, miR-15b, 24, 25 and 141 collectively target MAP2K4. The inflammatory interleukins IL6 and IL8 are secreted during stress-induced cellular senescence; miR-146a and b target and suppress these interleukins. Various miRNAs also regulate the p53 and Rb pathways. p53 activates expression of miR-34a, which targets and suppresses SIRT1 (as does miR-217), and SIRT1 normally deacetylates p53 and FOXO. Moreover, miR-29 suppresses the phosphatase PPM1D, which normally dephosphorylates p53. Furthermore, transcription of the CDK inhibitor p21 is correlated with downregulation of miR-15, miR-17, miR-19b, miR-20a and miR-106a and 106b. miR-22 targets CDK6, which then targets Rb. miR-29 and miR-30 repress the MYBL2 (B-Myb) oncogene, and their upregulation during senescence depends on Rb. The miR-17-92 cluster, as well as miR-21, miR-216a and miR-217, target PTEN, which normally blocks the phosphorylation cascade of the IIS pathway. miR-17-92 additionally target TGFβ, which also induces expression of miR-216a and miR-217. Further downstream in the IIS phosphorylation cascade, AKT induces downregulation of miR-199a-5p, which normally targets HIF1α and SIRT1. Finally, a few miRNAs regulate mitochondrial senescence-associated factors: miR-34a targets the antioxidative enzyme TXNRD2, and miR-335 targets superoxide dismutase 2 (SOD2), both of which are crucial for monitoring ROS generation.