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c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity
Open accessAbstract
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 p38 α 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.
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“p21 deficiency supports tissue regeneration, including complete rescue of regeneration of the impaired liver”
From p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling (2017) · cites this paper as Stepniak et al, 2006
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Metadata
- Authors
- Stepniak, E., Ricci, R., Eferl, R., Sumara, G., Sumara, I., Rath, M., Hui, L., & Wagner, E. F.
- Affiliations
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Wagner, Erwin F.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2006-08-15
- Volume
- 20
- Issue
- 16
- Pages
- 2306-2314
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1553212
- OpenAlex
- W2166342119
- Cited by
- 232
- References
- 43
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 13 · 2021: 15 · 2020: 8 · 2019: 15 · 2018: 7 · 2017: 15 · 2016: 8 · 2015: 13 · 2014: 11 · 2013: 9 · 2012: 14
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Marie Curie (CT 2001-01)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- c-Jun, AP-1 transcription factor, liver regeneration, partial hepatectomy, hepatocyte proliferation, p53, p21, p38 MAPK, p38α, cyclin-dependent kinase inhibitors, post-transcriptional regulation, conditional knockout mice, cell cycle arrest
- MeSH terms
- Animals, Female, Hepatectomy, Liver, Liver Regeneration, Male, Phosphorylation, Protein Processing, Post-Translational, RNA Processing, Post-Transcriptional, Signal Transduction, Genes, p53, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-jun, Genes, jun, Gene Deletion, Mice, Knockout, Transcription Factor AP-1, Hepatocytes, p38 Mitogen-Activated Protein Kinases, Cyclin-Dependent Kinase Inhibitor p21, Mice
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