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Signaling and Regulation

Differential Transcription-Coupled Translational Inhibition of Human p53 Expression: A Potentially Important Mechanism of Regulating p53 Expression in Normal versus Tumor Tissue¹

¹ Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA;
² Departments of Interdisciplinary Oncology, ³ Biochemistry and Molecular Biology, and ⁴ Pharmacology and Therapeutics, Cancer Epidemiology and Prevention Program, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL

Requests for reprints: Philip Lazarus, H. Lee Moffitt Cancer Center, MRC-2E, Room 2067D, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612. Phone: (813) 903-6820; Fax: (813) 632-1328. E-mail: plazarus{at}moffitt.usf.edu

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.