| Summary: | 碩士 === 國立臺灣大學 === 生化科學研究所 === 97 === Tumor necrosis factor (TNF)-α is a cytokine involved in systemic inflammation, and is a member of a group of cytokines that stimulate the acute phase reaction. In this study, we focus on the regulatory mechanism of two TNF-α induced genes, cyclooxygenase-2 (COX-2) and Tristetraprolin (TTP). Using NIH3T3 cell line as a model, we found that COX-2 mRNA was activated by TNF-α treatment, and histone deacetylase inhibitor (HDACi) TSA could significantly block COX-2 activation. In addition, TNFα induced COX-2 expression could be inhibited by NFκB inhibitor BAY to a similar level as TSA. This indicated that NFκB signaling pathway may play an important role in modulating COX-2 expression. However, effects of TSA were not on NFκB nucleocytoplasmic distribution or DNA-binding ability. Results of chromatin immunoprecipitation (ChIP) assay revealed that TSA impaired COX-2 mRNA production by suppressing polymerase II elongation on the cox-2 gene. Further investigation on the molecular mechanism of this action would help to understand how HDACi suppressed gene expression. Another focus of this study is about the transient stabilization of TTP mRNA in response to TNF-α stimulation. We investigated the role of 3’untranslated region (UTR) in the regulation mechanism of TTP, and we found that the AU-rich element (ARE) was crucial for TTP expression modulation in the post-transcriptional level. Nevertheless, related works are still ongoing to explore the signaling cascade involved in transient TTP mRNA accumulation.
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