Abstract
Upon activation by liver injury, hepatic stellate cells produce excessive fibrous tissue leading to cirrhosis. The hepatotoxin CCl(4) induced activation of RSK, phosphorylation of C/EBPbeta on Thr(217), and proliferation of stellate cells in normal mice, but caused apoptosis of these cells in C/EBPbeta-/- or C/EBPbeta-Ala(217) (a dominant-negative nonphosphorylatable mutant) transgenic mice. Both C/EBPbeta-PThr(217) and the phosphorylation mimic C/EBPbeta-Glu(217), but not C/EBPbeta-Ala(217), were associated with procaspases 1 and 8 in vivo and in vitro and inhibited their activation. Our data suggest that C/EBPbeta phosphorylation on Thr(217) creates a functional XEXD caspase substrate/inhibitor box (K-Phospho-T(217)VD) that is mimicked by C/EBPbeta-Glu(217) (KE(217)VD). C/EBPbeta-/- and C/EBPbeta-Ala(217) stellate cells were rescued from apoptosis by the cell permeant KE(217)VD tetrapeptide or C/EBPbeta-Glu(217).
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcysteine / analogs & derivatives*
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Acetylcysteine / pharmacology
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Amino Acid Motifs
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Animals
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Apoptosis / physiology
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism*
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Carbon Tetrachloride / toxicity
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Caspase Inhibitors
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Caspases / metabolism*
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Cell Survival / physiology*
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Cells, Cultured
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Culture Media, Serum-Free
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Enzyme Activation
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Enzyme Precursors / metabolism
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / physiology*
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Humans
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Liver Cirrhosis, Experimental / chemically induced
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Male
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Mice
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Mice, Transgenic
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Microscopy, Confocal
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Phosphorylation
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Rats
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Ribosomal Protein S6 Kinases / genetics
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Ribosomal Protein S6 Kinases / metabolism*
Substances
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CCAAT-Enhancer-Binding Protein-beta
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Caspase Inhibitors
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Culture Media, Serum-Free
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Enzyme Precursors
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Recombinant Proteins
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lactacystin
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Carbon Tetrachloride
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Ribosomal Protein S6 Kinases
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Caspases
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Acetylcysteine