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Cited by 52Liver physiology and pathologyCancer-related Molecular PathwaysWnt/β-catenin signaling in development and cancer

c-Fos overexpression increases the proliferation of human hepatocytes by stabilizing nuclear Cyclin D1

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Güller, Meryem, Toualbi-Abed, Kahina, Legrand, Agnès, Michel, Laurence, Mauviel, Alain, Bernuau, Dominique, Daniel, Fanny·2008·World Journal of Gastroenterology
DOI 10.3748/wjg.14.6339PMC PMC2766115
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Abstract

AIM: To investigate the effect of stable c-Fos overexpression on immortalized human hepatocyte (IHH) proliferation. METHODS: IHHs stably transfected with c-Fos (IHH-Fos) or an empty vector (IHH-C) were grown in medium supplemented with 1% serum or stimulated with 10% serum. Cell proliferation was assessed by cell counts, 3H-thymidine uptake and flow cytometry analyses. The levels of cell cycle regulatory proteins (Cyclin D1, E, A) cyclin dependent kinases (cdk) cdk2, cdk4, cdk6, and their inhibitors p15, p16, p21, p27, total and phosphorylated GSK-3beta and epidermal growth factor receptor (EGF-R) were assayed by Western blotting. Analysis of Cyclin D1 mRNA levels was performed by reverse transcription-polymerase chain reaction and real-time polymerase chain reaction (PCR) analysis. Stability of Cyclin D1 was studied by cycloheximide blockade experiments. RESULTS: Stable c-Fos overexpression increased cell proliferation under low serum conditions and resulted in a two-fold increase in [3H]-thymidine incorporation following serum addition. Cell cycle analysis by flow cytometry showed that c-Fos accelerated the cell cycle kinetics. Following serum stimulation, Cyclin D1 was more abundantly expressed in c-Fos overexpressing cells. Cyclin D1 accumulation did not result from increased transcriptional activation, but from nuclear stabilization. Overexpression of c-Fos correlated with higher nuclear levels of inactive phosphorylated GSK-3beta, a kinase involved in Cyclin D1 degradation and higher levels of EGF-R mRNA, and EGF-R protein compared to IHH-C both in serum starved, and in serum stimulated cells. Abrogation of EGF-R signalling in IHH-Fos by treatment with AG1478, a specific EGF-R tyrosine kinase inhibitor, prevented the phosphorylation of GSK-3beta induced by serum stimulation and decreased Cyclin D1 stability in the nucleus. CONCLUSION: Our results clearly indicate a positive role for c-Fos in cell cycle regulation in hepatocytes. Importantly, we delineate a new mechanism by which c-Fos could contribute to hepatocarcinogenesis through stabilization of Cyclin D1 within the nucleus, evoking a new feature to c-Fos implication in hepatocellular carcinoma.

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  • c-fos expression after PHx is dependent on presence of senescent cells and ERK activation.

    “the expression of c-fos, an ERK-regulated gene that can promote hepatocyte cell cycle reentry through the regulation of cyclin D1 (59, 60), was elevated after PHx but eliminated by ABT263 or SCH772984, indicating that c-fos expression after PHx is dependent on the presence of senescent cells and ERK activation”

    From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [60]

    The Discussion (page unavailable) reports that c-Fos overexpression promotes hepatocyte cell-cycle progression by stabilizing nuclear Cyclin D1. The paper does not establish that c-fos expression is ERK-regulated. The citation appears before the citing authors’ PHx and senescent-cell conclusion, which should not be attributed to this source. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Güller, M., Toualbi-Abed, K., Legrand, A., Michel, L., Mauviel, A., Bernuau, D., & Daniel, F.
Affiliations
Inserm (FR)
ORCID
Venue
World Journal of Gastroenterology
Publisher
Baishideng Publishing Group Inc.
Published
2008
Volume
14
Issue
41
Pages
6339
ISSN
1007-9327 (ISSN-L)
DOI
10.3748/wjg.14.6339
PMC
PMC2766115
OpenAlex
W2097915084
Cited by
52
References
3
Citations by year
2026: 8 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 1 · 2016: 6 · 2015: 2 · 2014: 6 · 2013: 4 · 2012: 1
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • World Journal of Gastroenterology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
c-fos, cyclin D1, hepatocyte proliferation, protein stabilization, GSK3β, epidermal growth factor receptor, cell cycle regulation, hepatocarcinogenesis, hepatocellular carcinoma, cyclin-dependent kinases
MeSH terms
Glycogen Synthase Kinase 3 beta, Cell Cycle, Cell Nucleus, Cell Transformation, Neoplastic, Cells, Cultured, Cycloheximide, Humans, Kinetics, Phosphorylation, Protein Synthesis Inhibitors, Quinazolines, RNA, Messenger, Transfection, Up-Regulation, Proto-Oncogene Proteins c-fos, Cyclin-Dependent Kinases, Cyclin D1, Tyrphostins, Hepatocytes, Glycogen Synthase Kinase 3, Protein Kinase Inhibitors, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor Proteins, Protein Stability, ErbB Receptors

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