c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity
- Ewa Stepniak1,
- Romeo Ricci1,2,
- Robert Eferl1,3,
- Grzegorz Sumara2,
- Izabela Sumara4,
- Martina Rath,
- Lijian Hui, and
- Erwin F. Wagner5
Abstract
The AP-1 transcription factor c-Jun is a key regulator of hepatocyte proliferation. Mice lacking c-Jun in the liver (c-jun Δli*) 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 Δli* mice abrogated both hepatocyte cell cycle block and increased p21 protein expression. Consistently, liver regeneration was rescued in c-jun Δli* 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 Δli* 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 Δli* mice. Importantly, conditional deletion of p38α in livers of c-jun Δli* 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 p38α.
Keywords
Footnotes
-
↵1 These authors contributed equally to this work.
-
↵2 Present addresses: ETH Zürich (Hönggerberg), Institute of Cell Biology, Schafmattstr. 18, CH-8093 Zürich, Switzerland;
-
↵3 Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Währinger Strasse 13a, A-1090 Vienna, Austria;
-
↵4 ETH Zürich (Hönggerberg), Institute of Biochemistry, Schafmattstr. 18, CH-8093 Zürich, Switzerland.
-
↵5 Corresponding author.
↵5 E-MAIL wagner{at}imp.univie.ac.at; FAX 43-1-7989370.
-
Supplemental material is available at http://www.genesdev.org.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.390506.
-
- Received April 12, 2006.
- Accepted June 1, 2006.
- Copyright © 2006, Cold Spring Harbor Laboratory Press