Tumor Suppressor Protein Pdcd4 Inhibits Translation of p53 mRNA

The tumor suppressor protein Pdcd4 is thought to suppress translation of mRNAs containing structured 5′-UTRs by interacting with translation initiation factor eIF4A and inhibiting its helicase activity. However, natural target mRNAs regulated by Pdcd4 so far are mostly unknown. Here, we identified p53 mRNA as a translational target of Pdcd4. We found that Pdcd4 is associated with p53 mRNA and suppresses its translation. The inhibitory effect of Pdcd4 on the translation of p53 mRNA depends on the ability of Pdcd4 to interact with eIF4A and is mediated by the 5′-UTR of p53 mRNA, which is able to form a stable stem-loop structure. We show that treatment of cells with DNA-damaging agents decreases the expression of Pdcd4. This suggests that translational suppression by Pdcd4 plays a role in maintaining a low level of p53 in unstressed cells and that this suppression is abrogated due to low levels of Pdcd4 after DNA damage. Overall, our work demonstrates for the first time that Pdcd4 is directly involved in translational suppression of a natural mRNA with a 5′-structured UTR and provides novel insight into the translational control of p53 expression. Background: Pdcd4 is a tumor suppressor involved in translational regulation. Results: Pdcd4 interacts with p53 mRNA and inhibits its translation via the 5′-UTR. Under stress conditions, the expression of Pdcd4 decreases. Conclusion: Translation of p53 mRNA is suppressed by Pdcd4 under normal growth conditions. Significance: Pdcd4 is a new translational regulator of p53.