The EGF receptor is required for efficient liver regeneration
The EGF receptor is required for efficient liver regeneration
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DOI：
10.1073/pnas.0704126104
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发表时间：
2007-10-23
影响因子：
11.1
通讯作者：
Sibilia, Maria
中科院分区：
文献类型：
--
作者：
Natarajan, Anuradha;Wagner, Bettina;Sibilia, Maria
缺乏表皮生长因子受体（EGFR）的小鼠在妊娠中期和出生后20天之间死亡，神经和上皮器官有各种缺陷。在这里，我们产生了携带floxed EGFR等位基因的小鼠，以在胎儿和成人肝脏中抑制EGFR。围产期肝细胞中EGFR缺失导致体重下降，而成年肝脏中EGFR缺失不影响体重。虽然肝功能不受影响，但在部分肝切除术后，肝脏中缺乏EGFR的小鼠显示死亡率增加，伴有血清转氨酶水平升高，表明肝损伤。由于肝细胞增殖减少，肝再生在突变体中延迟。对EGFR缺陷肝脏细胞周期进程的分析表明，缺陷的G（1）-S期进入延迟的转录激活和减少的蛋白表达的细胞周期蛋白131，其次是减少cdk 2和cdk 1的表达。损伤的肝再生伴随着血清中TNF α的代偿性上调和c-Jun激活的延长。此外，p38 α和NF-κ B激活在再生突变肝中减少，表明肝切除术后应激反应受损。我们的研究表明，表皮生长因子受体是肝细胞增殖在肝再生的初始阶段的一个关键调节因子。
Mice lacking the EGF receptor (EGFR) die between midgestation and postnatal day 20 with various defects in neural and epithelial organs. Here, we generated mice carrying a floxed EGFR allele to inactivate the EGFR in fetal and adult liver. Perinatal deletion of EGFR in hepatocytes resulted in decreased body weight, whereas deletion in the adult liver did not affect body mass. Although liver function was not affected, after partial hepatectomy mice lacking EGFR in the liver showed increased mortality accompanied by increased levels of serum transaminases indicating liver damage. Liver regeneration was delayed in the mutants because of reduced hepatocyte proliferation. Analysis of cell cycle progression in EGFR-deficient livers indicated a defective G(1)-S phase entry with delayed transcriptional activation and reduced protein expression of cyclin 131 followed by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNF alpha in the serum and prolonged activation of c-Jun. Moreover, p38 alpha and NF-kappa B activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration.