p53 short peptide (p53 pep64) regulates lipopolysaccharide-induced tumor necrosis factor-a factor cytokine expression
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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 ofp53 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-nu11 H1299 cells. Transfection of p53pep164 into H1299 cells significantly down-regulated LPS-induced LITAF expression as well. Furthermore, transfection of p53pep1 64 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.
PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact firstname.lastname@example.org.Thesis (MSD)--Boston University, Goldman School of Dental Medicine, 2008 (Dept. of Periodontology and Oral Biology).Includes bibliographical references: leaves 31-35.
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