期刊
HEPATOLOGY
卷 48, 期 4, 页码 1302-1311出版社
WILEY
DOI: 10.1002/hep.22475
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资金
- NIDDK NIH HHS [U19 DK62434, F32DK063780, R01DK46546] Funding Source: Medline
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.
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