ZBTB20 regulates EGFR expression and hepatocyte proliferation in mouse liver regeneration.
ZBTB20 regulates EGFR expression and hepatocyte proliferation in mouse liver regeneration.
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ZBTB20在小鼠肝脏再生中调节EGFR表达和肝细胞增殖
DOI：
10.1038/s41419-018-0514-0
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Zhang WJ
中科院分区：
文献类型：
--
作者：
Zhang H;Shi JH;Jiang H;Wang K;Lu JY;Jiang X;Ma X;Chen YX;Ren AJ;Zheng J;Xie Z;Guo S;Xu X;Zhang WJ
肝脏具有独特的再生能力，但其调控机制尚未完全明确。我们已经建立了锌指蛋白ZBTB 20作为一个关键的转录抑制甲胎蛋白（AFP）基因在肝脏。AFP作为肝细胞分化的标志物，其表达与肝细胞增殖密切相关。出乎意料的是，在这里，我们发现ZBTB20作为肝脏复制的正调节因子，并且是有效的肝脏再生所必需的。肝细胞中特异性缺乏ZBTB 20的小鼠在部分肝切除术后表现出明显的肝再生缺陷，其特征在于肝细胞增殖受损沿着延迟的细胞周期蛋白D1诱导和减少的AKT活化。此外，我们发现，在不存在ZBTB20的情况下，肝脏中的上皮生长因子受体（EGFR）表达显著降低，从而显著减弱了再生肝脏中EGFR信号通路的激活。在ZBTB20缺陷肝细胞中，腺病毒介导的EGFR过表达可以在很大程度上恢复AKT对EGFR配体的体外激活，以及肝再生中的肝细胞复制。此外，ZBTB20过表达可显著恢复ZBTB20缺陷肝切除术后肝EGFR表达和细胞增殖。综上所述，我们的数据表明ZBTB20是小鼠肝再生中EGFR表达和肝细胞增殖的关键调节因子，并可能在肝再生的临床环境中作为潜在的治疗靶点。
Liver has a unique regenerative capacity, however, its regulatory mechanism is not fully defined. We have established the zinc-finger protein ZBTB20 as a key transcriptional repressor for alpha-fetoprotein (AFP) gene in liver. As a marker of hepatic differentiation, AFP expression is closely associated with hepatocyte proliferation. Unexpectedly, here we showed that ZBTB20 acts as a positive regulator of hepatic replication and is required for efficient liver regeneration. The mice specifically lacking ZBTB20 in hepatocytes exhibited a remarkable defect in liver regeneration after partial hepatectomy, which was characterized by impaired hepatocyte proliferation along with delayed cyclin D1 induction and diminished AKT activation. Furthermore, we found that epithelial growth factor receptor (EGFR) expression was dramatically reduced in the liver in the absence of ZBTB20, thereby substantially attenuating the activation of EGFR signaling pathway in regenerating liver. Adenovirus-mediated EGFR overexpression in ZBTB20-deficient hepatocytes could largely restore AKT activation in response to EGFR ligands in vitro, as well as hepatocyte replication in liver regeneration. Furthermore, ZBTB20 overexpression could significantly restore hepatic EGFR expression and cell proliferation after hepatectomy in ZBTB20-deficient liver. Taken together, our data point to ZBTB20 as a critical regulator of EGFR expression and hepatocyte proliferation in mouse liver regeneration, and may serve as a potential therapeutic target in clinical settings of liver regeneration.
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影响因子：
11.4
作者：
Behrens, A;Sibilia, M;Wagner, EF
通讯作者：
Wagner, EF
DOI：
10.1073/pnas.1301257110
发表时间：
2013-07-02
影响因子：
11.1
作者：
Liu, Xingguang;Zhang, Peng;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
13.5
作者：
Coutant, A;Rescan, C;Baffet, G
通讯作者：
Baffet, G
影响因子：
16.6
作者：
Nagao M;Ogata T;Sawada Y;Gotoh Y
通讯作者：
Gotoh Y
影响因子：
29.4
作者：
Berasain, C;García-Trevijano, ER;Avila, MA
通讯作者：
Avila, MA