Li J W, Wang G P, Fan J Y, Chang C F, Xu C S
College of Life Sciences, Henan Normal University, Xinxiang 453007, Henan Province, People's Republic of China.
J Genet. 2011 Dec;90(3):435-42.
Although it is known that hormones, growth factors and integrin promote hepatocyte proliferation in liver regeneration (LR) through ERK1/2 signalling pathway, reports about regulating processes of its intracellular paths in hepatocytes of LR are limited. This study aims at exploring which paths of ERK1/2 signalling pathway participate in the regulation of rat LR, especially in hepatocyte proliferation, and how they do so. In all, 14 paths and 165 genes are known to be involved in ERK1/2 signalling pathway. Of them, 161 genes are included in Rat Genome 230 2.0 Array. This array was used to detect expression changes of genes related to ERK1/2 signalling pathway in isolated hepatocytes of rat LR, showing that 60 genes were related to hepatocytes of LR. In addition, bioinformatics and systems biology methods were used to analyse the roles of 14 above paths in regenerating hepatocytes. We found that three paths, RTK→SHC→GRB2/SOS→RAS→RAF, IntegrinΒ→FAK→RAC→PAK→RAF and GΒγ→PI3KΒγ→RAC→PAK→RAF, promoted the G1 phase progression of hepatocytes by activating ERK1/2. A further four paths, Gq→PLCΒ→PKC→SRC/PYK2→GRB2/SOS→RAS→RAF, RTK→PLCγ→PKC→SRC/PYK2→GRB2/SOS→RAS→RAF, IntegrinΒ→FAK/SRC→GRB2/SOS→RAS→RAF and IntegrinΒ→FAK→RAC→PAK→RAF, advanced the cell progression of S phase and G(2)/M checkpoint by activating ERK1/2, and so did PP1/2→Mek1/2 by decreasing the negative influence on ERK1/2. At the late phase of LR, Gαs→AC→EPAC→Rap1→Raf blocked hepatocyte proliferation by decreasing the activity of ERK1/2 and so did PP1/2→Mek1/2. In summary, 60 genes and 8 paths of ERK1/2 signalling pathway regulated hepatocyte proliferation in rat LR.
尽管已知激素、生长因子和整合素通过ERK1/2信号通路促进肝再生（LR）过程中的肝细胞增殖，但关于其在LR肝细胞内信号通路调控过程的报道有限。本研究旨在探索ERK1/2信号通路的哪些途径参与大鼠LR的调控，尤其是在肝细胞增殖方面，以及它们是如何调控的。ERK1/2信号通路总共涉及14条途径和165个基因。其中，161个基因包含在大鼠基因组230 2.0芯片中。该芯片用于检测大鼠LR分离肝细胞中与ERK1/2信号通路相关基因的表达变化，结果显示60个基因与LR肝细胞相关。此外，采用生物信息学和系统生物学方法分析上述14条途径在再生肝细胞中的作用。我们发现，三条途径，即RTK→SHC→GRB2/SOS→RAS→RAF、整合素β→FAK→RAC→PAK→RAF和Gβγ→PI3Kβγ→RAC→PAK→RAF，通过激活ERK1/2促进肝细胞的G1期进程。另外四条途径，即Gq→PLCβ→PKC→SRC/PYK2→GRB2/SOS→RAS→RAF、RTK→PLCγ→PKC→SRC/PYK2→GRB2/SOS→RAS→RAF、整合素β→FAK/SRC→GRB2/SOS→RAS→RAF和整合素β→FAK→RAC→PAK→RAF，通过激活ERK1/2促进S期和G(2)/M期细胞进程，PP1/2→Mek1/2通过减少对ERK1/2的负面影响也起到了同样的作用。在LR后期，Gαs→AC→EPAC→Rap1→Raf通过降低ERK1/2的活性抑制肝细胞增殖，PP1/2→Mek1/2也有同样的作用。总之，ERK1/2信号通路的60个基因和8条途径调控大鼠LR中的肝细胞增殖。
