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Cancer Res. 2007 Feb 1;67(3):1308-16.

p53 short peptide (p53pep164) regulates lipopolysaccharide-induced tumor necrosis factor-alpha factor/cytokine expression.

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1
Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University Medical Center, 700 Albany Street, Boston, MA 02118, USA.

Abstract

The p53 protein is a sequence-specific DNA-binding factor that can induce apoptosis or activate genes whose dysregulation is involved in cancer. By using serial analysis of gene expression technique, p53-induced genes (PIGs) have been identified, one of which was lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) factor (LITAF/PIG7). LITAF regulates the transcription of cytokines such as TNF-alpha. To further elucidate the role of p53 in LITAF expression, LITAF promoter activity was carefully dissected. In this study, we found that the element required for transcriptional activity is mainly located in the region from -990 to -500 of the LITAF promoter; the specific site required for p53 protein-DNA binding is located between -550 and -500. We also found that transient transfection of either a p53 short DNA sequence, called p53LFB12, or its corresponding 7-amino-acid synthetic peptide from amino acids 164 to 170 (K164Q165S166Q167H168M169T170), named p53pep164, significantly reduced LITAF promoter activity to 15% in p53-null H1299 cells. Transfection of p53pep164 into H1299 cells significantly down-regulated LPS-induced LITAF expression as well. Furthermore, transfection of p53pep164 into human monocytes resulted in down-regulation of nine proinflammatory cytokines, including TNF-alpha. We also found that the LPS-activated p53 is a short-lived protein, and that p53-orchestrated apoptosis occurs shortly after the initiation stage following LPS stimulation and lasts a short time. Once p53 levels return to baseline, the p53-mediated inhibition of LITAF is released, and LITAF-mediated cytokine production can proceed. The present finding proposes a novel link between p53 and the inflammatory processes and highlights potential interventional approaches to control p53-associated inflammatory processes.

PMID:
17283168
DOI:
10.1158/0008-5472.CAN-06-1600
[Indexed for MEDLINE]
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