title: C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival.
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).
authors.affiliation: Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: M
authors.initials: M
authors.lastname: Buck
authors.forename: V
authors.initials: V
authors.lastname: Poli
authors.forename: T
authors.initials: T
authors.lastname: Hunter
authors.forename: M
authors.initials: M
authors.lastname: Chojkier
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000633:toxicity; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010766:Phosphorylation; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D061945:Caspase Inhibitors; D016895:Culture Media, Serum-Free; D004792:Enzyme Precursors; D011994:Recombinant Proteins; C067713:lactacystin; D002251:Carbon Tetrachloride; D019893:Ribosomal Protein S6 Kinases; D020169:Caspases; D000111:Acetylcysteine