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

Hepatology. 2008 Oct;48(4):1302-11. doi: 10.1002/hep.22475.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Constitutive Androstane Receptor
  • Disease Models, Animal
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / metabolism*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hyperplasia / chemically induced
  • Hyperplasia / metabolism
  • Hyperplasia / pathology
  • Liver / metabolism*
  • Liver / pathology*
  • Liver / physiopathology
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Pyridines
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction
  • Transcription Factors / agonists
  • Transcription Factors / metabolism*


  • Constitutive Androstane Receptor
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • Myc protein, mouse
  • Nr1i3 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Pyridines
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • 1,4-bis(2-(3,5-dichloropyridyloxy))benzene