Implication of transcriptional coactivator complexes in rheumatoid synovial cells

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To assess the implication of transcriptional coactivator in rheumatoid synoviocytes activation, we attempted the following two approaches. One is evaluation of nuclear acetylation, one of the critical roles as coactivator function of CREB binding protein (CBP). The other is molecular cloning of CBP-interaction proteins in rheumatoid synoviocytes by yeast two-hybrid systems.1) Using a specific antibody against acetylated lysine, we detected potent nuclear acetylation in rheumatoid synoviocytes and revealed that p53 is one of characteristically acetylated proteins. We further found that TNFα induced acetylation of p53 but attenuated its transcriptional activation in synoviocytes. As overexpression of CBP resulted in p53 promoter activation by TNFα, CBP recruitment is required for p53 activation.2) We cloned Notch-1 as one of CBP-binding proteins from cDNA library prepared from rheumatoid synoviocytes. Notch-1 signal was characteristically activated in rheumatoid synoviocytes though TNFα signaling and implicated in synoviocytes proliferation by TNFα.These results clearly suggested that coactivator takes crucial roles for rheumatoid synoviocytes activation and might contribute to clarifying the pathogenesis of RA.