Fig. 1

Schematic representation of the pathway activated by drug-induced perturbation of rRNA synthesis. Ribosomal proteins (RPs), no longer used for ribosome building, bind to MDM2, thus inhibiting its ubiquitin ligase activity toward p53 and the proteasome digestion of the tumor suppressor. As a consequence, p53 accumulates and induces transcription of p21, PUMA, and BAX. P21 is responsible for the cell cycle arrest by hindering pRb phosphorylation: in fact, hypo-phosphorylated pRb binds to and inhibits the activity of the transcription factor E2F1, whose target gene products are necessary for cell cycle progression. The induction of the pro-apoptotic factors PUMA and BAX activates the process of apoptotic cell death