PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival
PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival
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DOI：
10.1053/jhep.2002.36160
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发表时间：
2002-11-01
期刊：
影响因子：
13.5
通讯作者：
Baffet, G
中科院分区：
文献类型：
--
作者：
Coutant, A;Rescan, C;Baffet, G
已知生长因子有利于肝细胞的增殖和存活。在这项工作中，我们研究了两个主要的信号通路，磷酸肌醇3-激酶（PI 3 K）和丝裂原活化蛋白激酶（MEK）/细胞外信号调节激酶（ERK），在这些过程中的作用。首先，提供了PI 3 K级联以及MEK/ERK级联是控制肝细胞增殖的关键转导途径的证据，如通过在特异性PI 3 K抑制剂LY 294002存在下阻止DNA合成所确定的。雷帕霉素对FRAP/mTOR的抑制也废除了生长因子诱导的DNA复制和蛋白质合成。我们发现，在信使RNA（mRNA）和蛋白质水平的细胞周期蛋白D1的表达受到这一途径的调节。我们强调，4 E-BP 1磷酸化不是由表皮生长因子（EGF）激活的，而是通过PI 3 K-FRAP/mTOR激活的胰岛素调节机制，这可以解释胰岛素对肝细胞增殖的许可作用。MEK/ERK通路与4 E-BP 1磷酸化之间无干扰，而EGF诱导的p70 S6 K磷酸化受U 0126敏感性调节。最后，我们确定EGF的抗凋亡功能依赖于MEK，而LY 294002和雷帕霉素对细胞存活没有直接影响。总之，这些数据突出了通过作用于不同步骤介导生长相关反应的2种途径的调节和作用。总之，EGF诱导的G1期晚期肝细胞进展产生依赖于MEK激活的存活信号，而PI 3 K和MEK/ERK级联都是肝细胞复制所必需的。
Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication.