Dixon M, Agius L, Yeaman S J, Day C P
Centre for Liver Research, University of Newcastle, Newcastle upon Tyne, UK.
Hepatology. 1999 May;29(5):1418-24. doi: 10.1002/hep.510290516.
Stimulation of hepatocyte proliferation by epidermal growth factor (EGF) and insulin is inhibited by transforming growth factor beta (TGF-beta) and by glucagon. It is also suppressed by inhibitors of various protein kinases, including rapamycin, which blocks activation of p70 S6 kinase (p70(S6k)), PD98059, which inhibits the activation of extracellular-regulated kinase (ERK), and SB 203580, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated whether the inhibition of proliferation by TGF-beta involves these protein kinase cascades. Culture of hepatocytes with TGF-beta for 16 hours decreased the stimulation by EGF of ERK2 and p70(S6k) (by 50% and 35%, respectively), but did not affect the stimulation of either p38 MAPK, c-jun NH2-terminal kinase (JNK), or protein kinase B (PKB). Culture of hepatocytes with glucagon for 16 hours also inhibited the stimulation by EGF of activation of ERK2 and p70(S6k) (by approximately 50%). The inhibitory effects of glucagon were observed when the hormone was added either 10 minutes or 60 minutes before EGF addition, whereas no effects of TGF-beta were observed after 10-minute or 60-minute incubation. These results suggest that the inhibition of hepatocyte proliferation by TGF-beta may be in part mediated by inhibition of ERK2 and p70(S6k), but does not involve PKB, JNK, or p38 MAPK. Unlike glucagon, the effects of TGF-beta are not elicited in response to short-term treatment.
表皮生长因子（EGF）和胰岛素对肝细胞增殖的刺激作用会受到转化生长因子β（TGF-β）和胰高血糖素的抑制。它还会被各种蛋白激酶的抑制剂所抑制，包括雷帕霉素（可阻断p70 S6激酶（p70(S6k)）的激活）、PD98059（可抑制细胞外调节激酶（ERK）的激活）以及SB 203580（p38丝裂原活化蛋白激酶（p38 MAPK）的抑制剂）。在本研究中，我们调查了TGF-β对增殖的抑制作用是否涉及这些蛋白激酶级联反应。用TGF-β培养肝细胞16小时可降低EGF对ERK2和p70(S6k)的刺激作用（分别降低50%和35%），但不影响对p38 MAPK、c-jun NH2末端激酶（JNK）或蛋白激酶B（PKB）的刺激作用。用胰高血糖素培养肝细胞16小时也会抑制EGF对ERK2和p70(S6k)激活的刺激作用（约50%）。当在添加EGF前10分钟或60分钟添加该激素时，可观察到胰高血糖素的抑制作用，而在10分钟或60分钟孵育后未观察到TGF-β的作用。这些结果表明，TGF-β对肝细胞增殖的抑制作用可能部分是由对ERK2和p70(S6k)的抑制介导的，但不涉及PKB、JNK或p38 MAPK。与胰高血糖素不同，TGF-β的作用不是由短期处理引起的。
