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.


CONCLUSIONS
Collectively, this study identifies c-Myc and FoxM1 mediated proliferative programs as key mediators of TCPOBOP-CAR induced direct liver hyperplasia.
Blanco-Bose
William E
WE
Genetics & Stem Cell Laboratory, Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC-Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland.
Murphy
Mark J
MJ
Ehninger
Armin
A
Offner
Sandra
S
Dubey
Christelle
C
Huang
Wendong
W
Moore
David D
DD
Trumpp
Andreas
A
D000818:Animals; D049109:Cell Proliferation; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*
D000090702:Constitutive Androstane Receptor; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; C489428:Myc protein, mouse; C000716328:Nr1i3 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene