Impaired hepatocyte DNA synthetic response posthepatectomy in insulin-like growth factor binding protein 1-deficient mice with defects in C/EBPβ and mitogen-activated protein kinase/extracellular signal-regulate kinase regulation
Impaired hepatocyte DNA synthetic response posthepatectomy in insulin-like growth factor binding protein 1-deficient mice with defects in C/EBPβ and mitogen-activated protein kinase/extracellular signal-regulate kinase regulation
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DOI：
10.1128/mcb.23.4.1251-1259.2003
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发表时间：
2003-02-01
影响因子：
5.3
通讯作者：
Taub, R
中科院分区：
文献类型：
--
作者：
Leu, JI;Crissey, MAS;Taub, R
在三分之二的肝切除术后，正常静止的肝细胞被刺激重新进入细胞周期并增殖以恢复原始的肝脏质量。再生肝脏中最快速和高度诱导的基因和蛋白质之一是胰岛素样生长因子结合蛋白1（IGFBP-1），其是一种分泌蛋白，可以调节胰岛素样生长因子（IGF）的活性或通过IGF非依赖性机制发出信号。为了评估IGFBP-I在肝再生中的功能作用，产生了具有IGFBP-I基因的靶向破坏的小鼠。虽然IGFBP-1（-/-）小鼠表现出正常的发育，但它们在部分肝切除术后出现异常的肝再生，其特征是肝坏死和肝细胞DNA合成减少和延迟。异常的再生反应与有丝分裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）的钝化激活和C/EBP β蛋白表达的诱导减少有关。与肝切除C/EBP beta（-/-）小鼠中观察到的细胞周期异常一样，IGFBP-1（-/-）肝脏中细胞周期蛋白A和细胞周期蛋白B1的表达延迟和减少，而细胞周期蛋白D1的表达正常。用术前剂量的IGFBP-1治疗IGFBP-1（-/-）小鼠可诱导MAPK/ERK激活和C/EBP β表达，这表明IGFBP-1可能至少部分通过其对MAPK/ERK和C/EBP β活性的影响来支持肝脏再生。这些发现首次证明IGFBP-1参与体内促有丝分裂信号通路的调节。
After a two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. One of the most rapidly and highly induced genes and proteins in regenerating liver is insulin-like growth factor binding protein 1 (IGFBP-1), a secreted protein that may modulate the activities of insulin-like growth factors (IGFs) or signal via IGF-independent mechanisms. To assess the functional role of IGFBP-1 in liver regeneration, mice with a targeted disruption of the IGFBP-1 gene were generated. Although IGFBP-1(-/-) mice demonstrated normal development, they had abnormal liver regeneration after partial hepatectomy, characterized by liver necrosis and reduced and delayed hepatocyte DNA synthesis. The abnormal regenerative response was associated with blunted activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and a reduced induction of C/EBPbeta protein expression posthepatectomy. Like cell cycle abnormalities observed in hepatectomized C/EBPbeta(-/-) mice, cyclin A and cyclin B1 expression was delayed and reduced in IGFBP-1(-/-) livers, whereas cyclin D1 expression was normal. Treatment of IGFBP-1(-/-) mice with a preoperative dose of IGFBP-1 induced MAPK/ERK activation and C/EBPbeta expression, suggesting that IGFBP-1 may support liver regeneration at least in part via its effect on MAPK/ERK and C/EBPbeta activities. These findings are the first demonstration of the involvement of IGFBP-1 in the regulation of in vivo mitogenic signaling pathways.