CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy.

Greenbaum, L E; Li, W; Cressman, D E; Peng, Y; Ciliberto, G; Poli, V; Taub, R

doi:10.1172/jci3135

Cited by 270Liver physiology and pathologyOrgan Transplantation Techniques and OutcomesTissue Engineering and Regenerative Medicine

CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy.

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Greenbaum, L E, Li, W, Cressman, D E, Peng, Y, Ciliberto, G, Poli, V, Taub, R·1998·Journal of Clinical Investigation

DOI 10.1172/jci3135PMC PMC508965

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Abstract

After two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. The level of bZIP transcription factor CCAAT enhancer-binding protein beta (C/EBPbeta) increases in the liver during the period of cell proliferation. The significance of this change in C/EBP expression is not understood. To determine the role of C/EBPbeta in the regenerating liver, we examined the regenerative response after partial hepatectomy in mice that contain a targeted disruption of the C/EBPbeta gene. Posthepatectomy, hepatocyte DNA synthesis was decreased to 25% of normal in C/EBPbeta -/- mice. The reduced regenerative response was associated with a prolonged period of hypoglycemia that was independent of expression of C/EBPalpha protein and gluconeogenic genes. C/EBPbeta -/- livers showed reduced expression of immediate-early growth-control genes including the Egr-1 transcription factor, mitogen-activated protein kinase protein tyrosine phosphatase (MKP-1), and HRS, a delayed-early gene that encodes an mRNA splicing protein. Cyclin B and E gene expression were dramatically reduced in C/EBPbeta -/- livers whereas cyclin D1 expression was normal. The abnormalities in immediate-early gene expression in C/EBPbeta -/- livers were distinct from those seen in IL-6 -/- livers. These data link C/EBPbeta to the activation of metabolic and growth response pathways in the regenerating liver and demonstrate that C/EBPbeta is required for a normal proliferative response.

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Regaining liver mass despite deficient DNA synthesis is a general phenomenon in animal models defective in liver regeneration, most likely resulting from hypertrophy of hepatocytes despite G1/S arrest.
“Regaining liver mass despite deficient DNA synthesis is a general phenomenon in animal models that are defective in liver regeneration, which most likely results from hypertrophy of hepatocytes despite G1/S arrest (3”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [18]
The Results report markedly reduced DNA synthesis in C/EBPβ-deficient mice without a statistically significant difference in liver-mass reconstitution. The Discussion proposes increased cell size during G1 as an explanation and suggests that the cell-cycle block may occur near G1/S. It does not establish this as a general phenomenon across animal models or demonstrate hepatocyte hypertrophy despite a confirmed G1/S arrest. (LLM, conf=0.86)
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Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice
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Disrupted signaling and inhibited regeneration in obese mice with fatty livers: Implications for nonalcoholic fatty liver disease pathophysiology
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Disruption of Hepatic Adipogenesis Is Associated With Impaired Liver Regeneration in Mice
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Inhibition of Albumin Synthesis in Chronic Diseases
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C/EBPδ regulates cell cycle and self-renewal of human limbal stem cells
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Foxa2 and H2A.Z Mediate Nucleosome Depletion during Embryonic Stem Cell Differentiation
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CCAAT/enhancer-binding protein β: its role in breast cancer and associations with receptor tyrosine kinases
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Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes
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Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells
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Genomics of the Periinfarction Cortex after Focal Cerebral Ischemia
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Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase
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Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes
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Phosphorylation of Rat Serine 105 or Mouse Threonine 217 in C/EBPβ Is Required for Hepatocyte Proliferation Induced by TGFα
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A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #
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C/EBPβ is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma
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C/EBPβ cooperates with RB:E2F to implement RasV12‐induced cellular senescence
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Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice
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FoxF1 and FoxL1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine
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C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease
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Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration
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Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver
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Massive hepatic apoptosis associated with TGF-β1 activation after Fas ligand treatment of IGF binding protein-1–deficient mice
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Identification of Transcriptional Networks during Liver Regeneration
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Concerted Functions of Gab1 and Shp2 in Liver Regeneration and Hepatoprotection
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Impaired Hepatocyte DNA Synthetic Response Posthepatectomy in Insulin-Like Growth Factor Binding Protein 1-Deficient Mice with Defects in C/EBPβ and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Regulation
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C/EBPα Regulates Generation of C/EBPβ Isoforms through Activation of Specific Proteolytic Cleavage
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The Role of C/EBPβ in Mammary Gland Development and Breast Cancer
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The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation
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G9a-mediated Lysine Methylation Alters the Function of CCAAT/Enhancer-binding Protein-β
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CCAAT/Enhancer-Binding Protein Mediates Carbon Monoxide–Induced Suppression of Cyclooxygenase-2
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CCAAT/enhancer binding proteins in normal mammary development and breast cancer
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Nuclear export of phosphorylated C/EBPβ mediates the inhibition of albumin expression by TNF‐α
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Contribution of cyclooxygenase‐2 to liver regeneration after partial hepatectomy
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Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
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Delayed Hepatocellular Mitotic Progression and Impaired Liver Regeneration in Early Growth Response-1-deficient Mice
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p21 is required for dextrose-mediated inhibition of mouse liver regeneration #
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C/EBPβ ΔuORF mice—a genetic model for uORF-mediated translational control in mammalsPreprint
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Temporal mapping of CEBPA and CEBPB binding during liver regeneration reveals dynamic occupancy and specific regulatory codes for homeostatic and cell cycle gene batteriesPreprint
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Plasminogen Activators Direct Reorganization of the Liver Lobule after Acute Injury
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Reconstitution of Liver Mass Via Cellular Hypertrophy in the Rat
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O-Linked N-Acetylglucosamine Modification on CCAAT Enhancer-binding Protein β
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Transcription Factor Smad3 Is Required for the Inhibition of Adipogenesis by Retinoic Acid
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The nucleosome map of the mammalian liver
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Advances in the regulation of liver regeneration
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Transcription factor early growth response‐1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia
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C/EBPβ/AEP is age-dependently activated in Parkinson’s disease and mediates α-synuclein in the gut and brain
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Apigenin isolated from Daphne genkwa Siebold et Zucc. inhibits 3T3-L1 preadipocyte differentiation through a modulation of mitotic clonal expansion
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C/EBP β isoforms LIP and LAP modulate progression of the cell cycle in the regenerating mouse liver
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C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer’s disease
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CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice
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Normal Liver Regeneration in P50/Nuclear Factor κB1 Knockout Mice
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Regulation of hepatocyte identity and quiescence
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A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism.
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Authors: Greenbaum, L. E., Li, W., Cressman, D. E., Peng, Y., Ciliberto, G., Poli, V, & Taub, R.
Affiliations: University of Pennsylvania (US)
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
University of Dundee (GB)
ORCID: Peng, Y
Ciliberto, G
Poli, V
Taub, R
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1998-09-01
Volume: 102
Issue: 5
Pages: 996-1007
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci3135
PMC: PMC508965
OpenAlex: W2055209830
Cited by: 270
References: 72
Citations by year: 2026: 1 · 2025: 2 · 2024: 3 · 2023: 10 · 2022: 5 · 2021: 8 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 6 · 2016: 3 · 2015: 8 · 2014: 6 · 2013: 7 · 2012: 5
FWCI: 12.28
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders: National Institutes of Health (K08 DK, 5r01dk049629-05)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK044237, DK 44237, DK-49629, P01DK049210, DK 49210)
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords: C/EBPβ, hepatocyte proliferation, liver regeneration, partial hepatectomy, knockout mice, hypoglycemia, immediate early genes, EGR1, MKP-1, Hrs, cyclin B, cyclin E, cyclin D1, bZIP transcription factors, DNA synthesis
MeSH terms: Animals, Cell Division, Cells, Cultured, DNA, DNA-Binding Proteins, Gene Expression Regulation, Gluconeogenesis, Hepatectomy, Immunohistochemistry, Liver Regeneration, Nuclear Proteins, Phosphoproteins, RNA Splicing, RNA, Messenger, Transcription Factors, Trans-Activators, S Phase, Cyclins, Mice, Knockout, CCAAT-Enhancer-Binding Proteins, STAT3 Transcription Factor, Mice, Endosomal Sorting Complexes Required for Transport

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CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy.

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