Carmona-Cuenca Irene, Herrera Blanca, Ventura Juan-José, Roncero César, Fernández Margarita, Fabregat Isabel
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
J Cell Physiol. 2006 May;207(2):322-30. doi: 10.1002/jcp.20568.
Epidermal growth factor (EGF) is a survival signal for transforming growth factor-beta (TGF-beta)-induced apoptosis in hepatocytes, phosphatidylinositol 3-kinase (PI 3-K) being involved in this effect. Here, we analyze the possible cross talks between EGF and TGF-beta signals to understand how EGF impairs the early pro-apoptotic events induced by TGF-beta. Data have indicated that neither SMAD nor c-Jun NH2 Terminal Kinase (JNK) activations are altered by EGF, which clearly interferes with events directly related to the radical oxygen species (ROS) production, impairing oxidative stress, p38 MAP kinase activation, and cell death. Activation of a NADPH-oxidase-like system, which is responsible for the early ROS production by TGF-beta, is completely inhibited by EGF, through a PI 3-K-dependent mechanism. Activity of RAC1 increases by TGF-beta, but also by EGF, and both act synergistically to get maximum effects. Fetal rat hepatocytes express nox4, in addition to nox1 and nox2, and TGF-beta clearly upregulates nox4. EGF blocks up-regulation of nox4 by TGF-beta. Interestingly, in the presence of PI 3-K inhibitors, EGF is not able to counteract the nox4 upregulation by TGF-beta. Taking together these results indicate that impairment of TGF-beta-induced NADPH oxidase activation by EGF is a RAC1-independent process and correlates with an inhibition of the mechanisms that address the increase of nox4 mRNA levels by TGF-beta.
表皮生长因子（EGF）是肝细胞中转化生长因子-β（TGF-β）诱导凋亡的存活信号，磷脂酰肌醇3激酶（PI 3-K）参与此效应。在此，我们分析EGF与TGF-β信号之间可能的相互作用，以了解EGF如何损害TGF-β诱导的早期促凋亡事件。数据表明，EGF既不改变SMAD的激活，也不改变c-Jun氨基末端激酶（JNK）的激活，而EGF明显干扰与活性氧（ROS）产生直接相关的事件，损害氧化应激、p38丝裂原活化蛋白激酶激活和细胞死亡。负责TGF-β早期ROS产生的NADPH氧化酶样系统的激活被EGF通过PI 3-K依赖性机制完全抑制。RAC1的活性不仅被TGF-β增强，也被EGF增强，二者协同作用以产生最大效应。胎鼠肝细胞除了表达nox1和nox2外，还表达nox4，且TGF-β明显上调nox4。EGF可阻断TGF-β对nox4的上调作用。有趣的是，在存在PI 3-K抑制剂的情况下，EGF无法抵消TGF-β对nox4的上调作用。综合这些结果表明，EGF对TGF-β诱导的NADPH氧化酶激活的损害是一个不依赖RAC1的过程，并且与抑制TGF-β使nox4 mRNA水平升高的机制相关。
