c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity.
The AP-1 transcription factor c-Jun is a key regulator of hepatocyte proliferation. Mice lacking c-Jun in the liver (c-jun (Deltali*)) display impaired liver regeneration after partial hepatectomy (PH). This phenotype correlates with increased protein levels of the cdk-inhibitor p21 in the liver. We performed PH experiments in several double-knockout mouse models to genetically identify the signaling events regulated by c-Jun. Inactivation of p53 in c-jun (Deltali*) mice abrogated both hepatocyte cell cycle block and increased p21 protein expression. Consistently, liver regeneration was rescued in c-jun (Deltali*) p21 (-/-) double-mutant mice. This indicated that c-Jun controls hepatocyte proliferation by a p53/p21-dependent mechanism. Analyses of p21 mRNA and protein expression in livers of c-jun (Deltali*) mice after PH revealed that the accumulation of p21 protein is due to a post-transcriptional/post-translational mechanism. We have investigated several candidate pathways implicated in the regulation of p21 expression, and observed increased activity of the stress kinase p38 in regenerating livers of c-jun (Deltali*) mice. Importantly, conditional deletion of p38alpha in livers of c-jun (Deltali*) mice fully restored hepatocyte proliferation and attenuated increased p21 protein levels after PH. These data demonstrate that c-Jun/AP-1 regulates liver regeneration through a novel molecular pathway that involves p53, p21, and the stress kinase p38alpha.
Stepniak
Ewa
E
Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria.
Ricci
Romeo
R
Eferl
Robert
R
Sumara
Grzegorz
G
Sumara
Izabela
I
Rath
Martina
M
Hui
Lijian
L
Wagner
Erwin F
EF
D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D016758:Genes, jun; D016158:Genes, p53; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases