TNFα induces acetylation of p53 but attenuates its transcriptional activation in rheumatoid synoviocytes
Synovial hyperplasia is an important feature of rheumatoid arthritis (RA) and we have reported that several transcription factors were highly activated in rheumatoid synoviocytes. The purpose of this study was to examine nuclear acetylation in synoviocytes as an activation marker and determine its role in cell activation. Autonomous acetylation of approximately 53 and 62 kDa nuclear proteins was detected in rheumatoid synoviocytes by anti-acetylated lysine specific antibody. Furthermore, tumor necrosis factor α (TNFα), a potent mitogen for synoviocytes, dose-dependently increased their state of acetylation. Immunoprecipitation analysis revealed that 53 kDa acetylated protein (ap53) was identical with p53, a tumor suppressor gene product. Since enhanced p53 binding to the promoter by TNFα treatment was detected by gel shift assay, we analyzed p53 promoter activity by reporter assay system. Contrary to enhanced binding activity, the transcriptional activity was attenuated in a TNFα concentration-dependent manner. Since p53 activation requires recruitment of CREB binding protein (CBP) as a coactivator, we also examined the effect of CBP on TNFα-induced attenuation of p53 promoter activation. Overexpression of CBP induced p53 transcriptional activity and recovery of TNFα-induced inhibition. Our results clearly indicate that autonomous nuclear acetylation is characteristically enhanced in rheumatoid synoviocytes and that p53 is one of acetylated protein. Our results also demonstrate that TNFα-induced acetylation of p53 attenuated its transcriptional activation via CBP depletion, and that overexpression of CBP enhanced TNFα-induced cell death in rheumatoid synoviocytes, suggesting that regulation of transcriptional coactivator become a novel strategy for RA therapy.
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Document Type: Research Article
Affiliations: Rheumatology, Immunology and Genetics Program, Institute of Medical Science, St. Marianna University, School of Medicine, Kanagawa, Japan
Publication date: January 1, 2002
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- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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