Figure 7. Schematic of the signaling pathway activated by ribosomal stress.

Ribosomal stress, due to RP depletion, induces a decrease of PIM1 level that inhibits phosphorylation of AKT on Ser473; the consequent AKT inactivation causes a dephosphorylation of MDM2, inhibiting its nuclear import and ubiquitin ligase activity. This generates a stabilization of p53 that, through the feedback loop, induces an increase of total MDM2 level. The high level of MDM2 causes degradation of MDM4 which produces a further stabilization of p53. The final outcome of this signaling pathway is a p53-dependent cell growth inhibition.