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Media type:
E-Article
Title:
Identification and functional characterization of a novel binding site on TNF-α promoter
Contributor:
Tang, Xiaoren;
Fenton, Matthew J.;
Amar, Salomon
Published:
Proceedings of the National Academy of Sciences, 2003
Published in:
Proceedings of the National Academy of Sciences, 100 (2003) 7, Seite 4096-4101
Language:
English
DOI:
10.1073/pnas.0630562100
ISSN:
0027-8424;
1091-6490
Origination:
Footnote:
Description:
Transcription of the tumor necrosis factor (TNF) gene is rapidly and transiently induced by lipopolysaccharide in cells of monocyte/macrophage lineage. Previous studies have suggested that in the mouse, multiple NF-κB/Rel-binding sites contribute to the TNF transcriptional response to LPS. But the role of these regulatory elements in transcriptional activation of the TNF-α gene in human monocytes remains unclear. Previously, a transcription factor, termed lipopolysaccharide-induced TNF-α factor (LITAF), was found to regulate TNF-α gene expression. However, the specific protein domain(s) of human (h)LITAF that interact with the hTNF-α promoter had not been identified. In this study, we identify by footprinting a sequence motif, CTCCC (−515 to −511), within the TNF-α promoter that binds to hLITAF. We also identify the region of hLITAF (amino acids 165–180) that was named peptide B and specifically mediates binding to the hTNF-α promoter. When THP-1 cells were stimulated with this peptide B, it was sufficient to induce TNF-α secretion. Induction of TNF-α transcription by LPS or peptide B depended on the presence of the −515 to −511 promoter region, which was found to be essential for hLITAF binding. Together, these findings help to clarify the mechanism of hLITAF/hTNF-α interaction and the manner by which hLITAF contributes to hTNF-α regulation in an attempt to design new pharmacological interventions to address TNF-related diseases.