Differential transcription-coupled translational inhibition of human p53 expression: A potentially important mechanism of regulating p53 expression in normal versus tumor tissue

p53 protein accumulation is triggered following exposure to potentially carcinogenic DNA-damaging agents and other physiological processes. Here we show that although p53 mRNA transcribed from the downstream P₁ transcription start site was the only p53 transcript detected in human cell lines and tumor specimens, p53 transcripts initiated at the upstream P₀ and P₂ start sites were primary in normal human tissues, with P₀-initiated p53 transcripts comprising approximately 50% of total p53 transcripts. P₁-initiated p53 mRNA was not detected in most normal human tissues examined. Decreased translational efficiency was observed for mRNAs containing p53 5′ untranslated region sequences located between P₀ and P₁ in rabbit reticulocyte lysates and in cell lines; no inhibitory activity was observed for sequences located downstream of the P₁ start site. These data suggest that a transcriptional switch from P₀-/P₂- to P₁-initiated p53 mRNA could be an important mechanism by which cells regulate p53 expression.