| Summary: | 碩士 === 國立臺灣大學 === 藥理學研究所 === 96 === TGF-β regulates diverse biologic effects including cell growth, cell death or apoptosis, cell differentiation, and extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF), which is induced by TGF-β, has been reported to mediate stimulatory action of TGF-β-induced ECM. Although TNF-α was reported to suppress the TGF-β-induced CTGF gene expression, the molecular mechanism is not well- clarified. In this study, we found the inhibitory effect of TNF-α on TGF-β-induced CTGF expression in WT MEF cells, and the attenuation was abrogated in p65-/- MEF cells, suggesting the role of p65 in TNF-α-mediated inhibition. Long-term (8 hours) treatment of TNF-α induced the expression of inhibitory Smad (Smad7) and the inhibition of TGF-β-induced Smad2 phosphorylation, thereby inhibiting TGF-β signaling which were not seen in p65-/- MEF cells. Short-term (1 hours) treatment of TNF-α activated NF-κB, and p65 preferentially interacted with p300, thereby disrupting TGF-β-induced interaction of Smad4 with p300 on the CTGF promoter. Two molecular mechanisms of TNF-α inhibition are explored. One is the induction of Smad7 expression, and the other is the switch of binding preference of p300 from Smad4 to p65, thereby leading to the inhibition of TGF-β-induced CTGF expression.
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