American Association for Cancer Research
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Supplemental Fig. 5 from Nuclear Receptor CAR Suppresses GADD45B-p38 MAPK Signaling to Promote Phenobarbital-induced Proliferation in Mouse Liver

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journal contribution
posted on 2023-04-03, 16:40 authored by Takeshi Hori, Kosuke Saito, Rick Moore, Gordon P. Flake, Masahiko Negishi

Expression of the GADD45 (A, B, and G) and Cyp2b10 genes following PB treatment.


National Institute of Environmental Health Sciences



Phenobarbital, a nongenotoxic hepatocarcinogen, induces hepatic proliferation and promotes development of hepatocellular carcinoma (HCC) in rodents. Nuclear receptor constitutive active/androstane receptor (NR1I3/CAR) regulates the induction and promotion activities of phenobarbital. Here, it is demonstrated that phenobarbital treatment results in dephosphorylation of a tumor suppressor p38 MAPK in the liver of C57BL/6 and C3H/HeNCrlBR mice. The molecular mechanism entails CAR binding and inhibition of the growth arrest and DNA-damage-inducible 45 beta (GADD45B)-MAPK kinase 6 (MKK6) scaffold to repress phosphorylation of p38 MAPK. Phenobarbital-induced hepatocyte proliferation, as determined by BrdUrd incorporation, was significantly reduced in both male and female livers of GADD45B knockout (KO) mice compared with the wild-type mice. The phenobarbital-induced proliferation continued until 48 hours after phenobarbital injection in only the C57BL/6 males, but neither in males of GADD45B KO mice nor in females of C57BL/6 and GADD45B KO mice. Thus, these data reveal nuclear receptor CAR interacts with GADD45B to repress p38 MAPK signaling and elicit hepatocyte proliferation in male mice.Implications: This GADD45B-regulated male-predominant proliferation can be expanded as a phenobarbital promotion signal of HCC development in future studies.Visual Overview: Mol Cancer Res; 16(8); 1309–18. ©2018 AACR.

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