Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China.
Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing 400042, China.
Cell Signal. 2019 Mar;55:65-72. doi: 10.1016/j.cellsig.2018.12.013. Epub 2019 Jan 2.
Tmub1 (transmembrane and ubiquitin-like domain-containing 1) plays negative roles in rat hepatocyte proliferation, but its underlying molecular mechanisms in liver regeneration regulation have yet to be revealed. Here, we show that in vivo transfection of Tmub1 overexpression vectors impaired mouse liver regeneration after partial hepatectomy (PHx). Loss- and gain-of-function analyses in human hepatocyte Lo2 cells indicated that Tmub1 inhibits the phosphorylation of STAT3 and the activation of STAT3 signaling. Furthermore, the inhibitory effect of Tmub1 overexpression on hepatocyte proliferation can be reversed by the STAT3 activator OSM, while the promotive effect of Tmub1 knockdown can be abolished by the STAT3 inhibitor stattic. Coimmunoprecipitation assays revealed interaction between Tmub1 and STAT3. Finally, we present data from chromatin immunoprecipitation and luciferase reporter gene assays and report that STAT3 binds to and activates the promoter of Tmub1, suggesting a putative negative feedback loop between Tmub1 and STAT3 signaling. Taken together, the results of our study suggest that Tmub1 is an important negative regulator of hepatocyte proliferation in liver regeneration through STAT3 signaling. These findings provide a potential strategy for the management of liver regeneration.
Tmub1（跨膜和泛素样结构域蛋白 1）在大鼠肝细胞增殖中发挥负调控作用，但 Tmub1 调节肝再生的潜在分子机制尚不清楚。本研究显示，体内转染 Tmub1 过表达载体可损害小鼠肝部分切除（PHx）后的肝再生。在人肝细胞 Lo2 细胞中进行的缺失和获得功能分析表明，Tmub1 抑制 STAT3 的磷酸化和 STAT3 信号的激活。此外，Tmub1 过表达对肝细胞增殖的抑制作用可被 STAT3 激活剂 OSM 逆转，而 Tmub1 敲低的促进作用可被 STAT3 抑制剂 stattic 消除。免疫共沉淀实验揭示了 Tmub1 和 STAT3 之间的相互作用。最后，我们提供了染色质免疫沉淀和荧光素酶报告基因检测的数据，并报告 STAT3 结合并激活 Tmub1 的启动子，这表明 Tmub1 和 STAT3 信号之间存在潜在的负反馈环。综上所述，本研究结果表明，Tmub1 通过 STAT3 信号是肝再生中肝细胞增殖的重要负调控因子。这些发现为肝再生的管理提供了一种潜在的策略。
