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GENES & DEVELOPMENT 20:2306-2314, 2006
©2006 by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/ $5.00
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c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity

Ewa Stepniak ,1, Romeo Ricci ,1,2, Robert Eferl ,1,3, Grzegorz Sumara ,2, Izabela Sumara ,4, Martina Rath , Lijian Hui and Erwin F. Wagner ,5

Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria

The AP-1 transcription factor c-Jun is a key regulator of hepatocyte proliferation. Mice lacking c-Jun in the liver (c-jun {Delta}li*) 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 {Delta}li* mice abrogated both hepatocyte cell cycle block and increased p21 protein expression. Consistently, liver regeneration was rescued in c-jun {Delta}li* 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 {Delta}li* 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 {Delta}li* mice. Importantly, conditional deletion of p38{alpha} in livers of c-jun {Delta}li* 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 p38{alpha}.

[Keywords: c-Jun; p53; p21; p38/liver regeneration; partial hepatectomy]

Received April 12, 2006; revised version accepted June 1, 2006.

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.

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.


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