Two internal ribosome entry sites mediate the translation of p53 isoforms

The p53 tumour suppressor protein has a crucial role in cell-cycle arrest and apoptosis. Previous reports show that the p53 messenger RNA is translated to produce an amino-terminal-deleted isoform (Delta N-p53) from an internal initiation codon, which acts as a dominant-negative inhibitor of full-length p53. Here, we show that two internal ribosome entry sites (IRESs) mediate the translation of both full-length and Delta N-p53 isoforms. The IRES directing the translation of full-length p53 is in the 5'-untranslated region of the mRNA, whereas the IRES mediating the translation of Delta N-p53 extends into the protein-coding region. The two IRESs show distinct cell-cycle phase-dependent activity, with the IRES for full-length p53 being active at the G2-M transition and the IRES for Delta N-p53 showing highest activity at the G1-S transition. These results indicate a novel translational control of p53 gene expression and activity.