c-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia
c-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia
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DOI：
10.1002/hep.22475
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发表时间：
2008-10-01
期刊：
影响因子：
13.5
通讯作者：
Trumpp, Andreas
中科院分区：
文献类型：
--
作者：
Blanco-Bose, William E.;Murphy, Mark J.;Trumpp, Andreas
在成人肝脏中，1,4-双[2-(3,5-二氯吡啶氧基)]苯 (TCPOBOP) 是一种组成型雄甾烷受体 (CAR、NR1I3) 的激动剂，在没有损伤的情况下会导致快速肝肿大。在本研究中，我们将 c-Myc 鉴定为 CAR 诱导的基因，并证明 TCPOBOP 诱导的肝细胞增殖依赖于 c-Myc 功能。此外，TCPOBOP诱导的细胞周期程序（Cdc2、细胞周期蛋白、MCM蛋白、Cdc20和与纺锤体组装检查点有关的基因）在c-Myc突变肝脏中严重受损。引人注目的是，其中许多基因与叉头转录因子 FoxM1 控制的程序重叠，该因子已知控制 S 期和有丝分裂的进展。事实上，FoxM1 也是由 TCPOBOP 诱导的。此外，我们发现 c-Myc 以 TCPOBOP 依赖性方式与 FoxM1 启动子结合，表明 TCPOBOP 下游存在 CAR -> c-Myc -> FoxM1 通路。结论：总的来说，本研究确定 c-Myc 和 FoxM1 介导的增殖程序是 TCPOBOP-CAR 诱导的直接肝脏增生的关键介质。
In the adult liver, 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), an agonist of the constitutive androstane receptor (CAR, NR1I3), produces rapid hepatomegaly in the absence of injury. In this study, we identify c-Myc as a gene induced by CAR and demonstrate that TCPOBOP-induced proliferation of hepatocytes depends on c-Myc function. Moreover, the TCPOBOP-induced cell cycle program (Cdc2, cyclins, MCM proteins, Cdc20, and genes implicated in the spindle assembly checkpoint) is severely impaired in c-Myc mutant livers. Strikingly, many of these genes overlap with a program controlled by the forkhead transcription factor FoxM1, known to control progression through S-phase and mitosis. Indeed, FoxM1 is also induced by TCPOBOP. Moreover, we show that c-Myc binds to the FoxM1 promoter in a TCPOBOP-dependent manner, suggesting a CAR -> c-Myc -> FoxM1 pathway downstream of TCPOBOP. Conclusion: Collectively, this study identifies c-Myc and FoxM1 mediated proliferative programs as key mediators of TCPOBOP-CAR induced direct liver hyperplasia.