Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells

Hepatocellular carcinoma (HCC) usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage, hepatic stellate cells undergo progressive activation to myofibroblasts (MFB), which are important extracellular-matrix-producing mesenchymal cells. Concomitantly, perturbatio...

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Bibliographic Details
Published in:Cell and tissue research 2012-01, Vol.347 (1), p.225-243
Main Author: Matsuzaki, Koichi
Format: Article
Language:English
Subjects:
Activins - metabolism
Analysis
Animals
Biomedical and Life Sciences
Biomedicine
Bone morphogenetic proteins
carcinogenesis
carcinogenicity
Carcinoma, Hepatocellular - pathology
Carcinoma, Hepatocellular - physiopathology
Cellular biology
chemoprevention
Collagen
Cytokines
disease course
epithelial cells
Epithelial Cells - cytology
Epithelial Cells - physiology
fibrosis
hepatocytes
hepatoma
Human Genetics
Humans
Inflammation
JNK Mitogen-Activated Protein Kinases
kinases
Liver
Liver - injuries
Liver - physiology
Liver cancer
liver cirrhosis
Liver diseases
Liver Diseases - pathology
Liver Diseases - physiopathology
Liver Neoplasms - pathology
Liver Neoplasms - physiopathology
Mesoderm - cytology
Molecular Medicine
Pathogenesis
Phosphorylation
Phosphotransferases
Protein Isoforms - metabolism
Proteomics
receptors
Review
risk
Signal Transduction - physiology
Smad Proteins - metabolism
transforming growth factor beta
Transforming growth factors
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Summary:Hepatocellular carcinoma (HCC) usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage, hepatic stellate cells undergo progressive activation to myofibroblasts (MFB), which are important extracellular-matrix-producing mesenchymal cells. Concomitantly, perturbation of transforming growth factor (TGF)-β signaling by pro-inflammatory cytokines in the epithelial cells of the liver (hepatocytes) promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights into fibro-carcinogenic effects on chronically damaged hepatocytes have come from recent detailed analyses of the TGF-β signaling process. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create phosphoisoforms phosphorylated at the COOH-terminal, linker, or both (L/C) regions. After acute liver injury, TGF-β-mediated pSmad3C signaling terminates hepatocytic proliferation induced by the pro-inflammatory cytokine-mediated mitogenic pSmad3L pathway; TGF-β and pro-inflammatory cytokines synergistically enhance collagen synthesis by activated hepatic stellate cells via pSmad2L/C and pSmad3L/C pathways. During chronic liver disease progression, pre-neoplastic hepatocytes persistently affected by TGF-β together with pro-inflammatory cytokines come to exhibit the same carcinogenic (mitogenic) pSmad3L and fibrogenic pSmad2L/C signaling as do MFB, thereby accelerating liver fibrosis while increasing risk of HCC. This review of Smad phosphoisoform-mediated signals examines similarities and differences between epithelial and mesenchymal cells in acute and chronic liver injuries and considers Smad linker phosphorylation as a potential target for the chemoprevention of fibro-carcinogenesis.
ISSN:0302-766X
1432-0878
DOI:10.1007/s00441-011-1178-6