Regulation of p53 gene expression at the post-transcriptional level was investigated during growth induction of human peripheral blood mononuclear cells (PBMCs). Freshly isolated PBMCs, which are in the Go phase of the cell cycle, were shown to express low levels of p53 mRNA that was rapidly degraded with a half life of 1 h. The rapid decay of p53 mRNA in quiescent PBMCs was dependent on global protein synthesis as treatment with cycloheximide resulted in stabilization of the p53 message. PBMCs were stimulated to enter the cell cycle by treatment with a combination of the mitogenic lectin phytohemagglutinin (PHA) and phorbol ester (TPA). Progressive stabilization of the p53 message occurred in PBMCs during growth induction. By 24 h of incubation in the presence of PHA and TPA, the half life of p53 mRNA was 6 h and p53 mRNA steady state levels were increased 4.5 to 5.0-fold. p53 protein was not detected in quiescent PBMCs, but was readily detected in PBMCs stimulated for 24 h with PHA and TPA. Stabilization of p53 mRNA was observed in PBMCs treated with either PHA or TPA, but to a lesser degree than when PHA and TPA were used as co-stimulants. These results indicate that differential degradation of p53 messenger RNA occurs in quiescent vs mitogen stimulated PBMCs and suggest that post-transcriptional regulation importantly contributes to increased p53 mRNA steady state levels as PBMCs enter the cell cycle.