Figure 8. A graphical model.

(a) A model of p53 regulation in the absence of Six1 whereby RPL26 binds the 5′- and 3′-UTR of p53, leading to an increase in translation and p53 protein expression. The newly translated p53 regulates the transcription of genes that mediate tumour suppression. Downstream of RPL26-mediated increases in p53 translation, MDM2 acts to inhibit p53-mediated transcription and also to polyubiquitinate p53, targeting it for degradation through the proteasome. Nutlin-3 inhibits both of these effects of MDM2 on p53. (b) In the presence of Six1, there is a decrease in the amount of RPL26 bound to the p53 UTRs, allowing the Six1-regulated miRNA, miR-27a, to bind the p53 3′-UTR. This combined mechanism leads to a decrease in translation of p53, resulting in decreased p53-mediated transcription.