The role of protein kinase B and mitogen-activated protein kinase in epidermal growth factor and tumor necrosis factor α-mediated rat hepatocyte survival and apoptosis
The role of protein kinase B and mitogen-activated protein kinase in epidermal growth factor and tumor necrosis factor α-mediated rat hepatocyte survival and apoptosis
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DOI：
10.1002/hep.510310223
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发表时间：
2000-02-01
期刊：
影响因子：
13.5
通讯作者：
Cosulich, SC
中科院分区：
文献类型：
--
作者：
Roberts, RA;James, NH;Cosulich, SC
肝细胞生长调节的紊乱与许多肝脏疾病如纤维化和癌症有关。这些疾病是由调节肝细胞增殖和凋亡的生长因子和细胞因子网络介导的。在本研究中，我们研究了肿瘤坏死因子α (tnf - α)和表皮生长因子（EGF）激活的信号通路在转化生长因子β (tgf - β(1))诱导的细胞凋亡调控中的作用，因为这种生理因子被认为可以调节肝脏的自发凋亡。我们发现（10 ng/mL） EGF或（25 ng/mL） tnf - α预处理可分别抑制tgf - β(1)诱导的大鼠肝细胞凋亡73%和50%。然而，EGF和tnf - α对tgf - β(1)诱导的细胞凋亡的抑制是通过不同的蛋白激酶信号通路发生的。使用特异性抑制剂，我们发现EGF对细胞凋亡的抑制依赖于磷酸肌肽3激酶（PI 3激酶）和细胞外信号调节激酶（ERK）丝裂原活化蛋白（MAP）激酶途径的激活，而不是p38 MAP激酶。相反，tnf - α抑制tgf - β(1)诱导的细胞凋亡不需要PI 3-激酶和蛋白激酶B （PKB或Akt）介导的途径，而是依赖于ERK和p38 MAP激酶活性。这些数据有助于我们理解细胞内生存信号在正常肝脏稳态和不同病理条件下发挥的作用。
Perturbation of hepatocyte growth regulation is associated with a number of liver diseases such as fibrosis and cancer. These diseases are mediated by a network of growth factors and cytokines that regulate the induction of hepatocyte proliferation and apoptosis. In this study, we have investigated the role of signaling pathways activated by tumor necrosis factor alpha (TNF-alpha) and epidermal growth factor (EGF) in the regulation of apoptosis induced by transforming growth factor beta(1) (TGF-beta(1)), because this physiological factor is believed to regulate spontaneous apoptosis in the liver. We show that pretreatment with (10 ng/mL) EGF or (25 ng/mL) TNF-alpha can suppress TGF-beta(1)-induced apoptosis by 73% and 50%, respectively, in isolated rat hepatocytes, However, suppression of TGF-beta(1)-induced apoptosis by EGF and TNF-alpha occurs via different protein kinase signaling pathways. Using specific inhibitors, we show that suppression of apoptosis by EGF is dependent on activation of phosphoinositide 3-kinase (PI 3-kinase) and the extracellular signal regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathways, but not p38 MAP kinase. In contrast, suppression of TGF-beta(1)-induced apoptosis by TNF-alpha does not require PI 3-kinase and protein kinase B (PKB or Akt)-mediated pathways, but is dependent on ERK and p38 MAP kinase activity. These data contribute to our understanding of the intracellular survival signals that play a role in normal liver homeostasis and in diverse pathological conditions.