| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 101 === Liver fibrosis, a common scarring response to chronic liver injury, is associated with malfunction of transforming growth factor beta(TGFbeta) signaling. Previous studies have shown that prothymosin alpha (ProT) treatment restored the TGFbeta-induced immunosuppressive responses on monocytes and endothelial cells. To date, the role of ProT in TGFbeta signaling has not been characterized. We screened human liver cirrhosis tissue microarray and found higher ProT expression in human cirrhotic tissues than in normal ones, except hepatocytes. Regardless of TGFbetainduction, mouse embryonic fibroblasts (MEF) of ProT transgenic mice showed less phosphorylated smad2/3 which is key mediators of TGFbetasignaling. ProT expression level is associated with smad binding element (SBE)-mediated gene expression in MEF and human HepG2 hepatoma cells. To better define the role of ProT, we induced liver fibrosis in ProT transgenic mice by repetitive carbon-tetrachloride (CCl4) injections for 8 weeks. ProTtransgenic mice displayed less collagen type I accumulation, fibroblast specific protein-1 expressing cells, andalphasmooth muscle actin expression than wild-type mice after being exposed to CCl4. A reduced phosphorylated smad2/3 and an increase of smad7 protein, an antagonist of TGFbeta signaling pathway, were observed in liver tissues after CCl4 administration. Overexpression or knockdown of ProT in mouse primary hepatocytes and HepG2 cells showed that smad7 protein level, but not RNA level, was correlated with ProT expression. Smad7 was the major mediator of ProT inhibitory effect on SBE-mediated transcriptional activity, which downregulated p-smad2/3 and smad4 levels. ProTenhanced acetyltransferase p300-mediated acetylation on smad7, thereby maintaining the stability of smad7.Increased acetylated smad7 was also observed in liver homogenates of CCl4 treated ProT transgenic mice. The results of adenovirus-mediated gene delivery of ProT for CCl4-induced liver fibrosis in ICR mice were coincident with ProT transgenic mice. Collectively, our results demonstrate that ProT attenuated liver fibrosis through enhancing smad7 protein, which might be a potential therapeutic approach for liver fibrosis.
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