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C‐Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia

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. (HEPATOLOGY 2008.)