Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells
Open Access
- 31 May 2011
- journal article
- review article
- Published by Springer Science and Business Media LLC in Cell and tissue research
- Vol. 347 (1), 225-243
- https://doi.org/10.1007/s00441-011-1178-6
Abstract
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.Keywords
This publication has 128 references indexed in Scilit:
- Immunity, Inflammation, and CancerCell, 2010
- Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β PathwaysCell, 2009
- Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in miceHepatology, 2009
- Signaling cross-talk between TGF-β/BMP and other pathwaysCell Research, 2008
- TGFβ in CancerCell, 2008
- Liver regenerationJournal of Cellular Physiology, 2007
- Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2Cancer Cell, 2006
- TGF-β signaling: positive and negative effects on tumorigenesisCurrent Opinion in Genetics & Development, 2002
- A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized ratsGastroenterology, 1995
- TGF-β stimulation and inhibition of cell proliferation: New mechanistic insightsCell, 1990