C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival

Mol Cell. 2001 Oct;8(4):807-16. doi: 10.1016/s1097-2765(01)00374-4.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Amino Acid Motifs
  • Animals
  • Apoptosis / physiology
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Carbon Tetrachloride / toxicity
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Survival / physiology*
  • Cells, Cultured
  • Culture Media, Serum-Free
  • Enzyme Activation
  • Enzyme Precursors / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / physiology*
  • Humans
  • Liver Cirrhosis, Experimental / chemically induced
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • Phosphorylation
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ribosomal Protein S6 Kinases / genetics
  • Ribosomal Protein S6 Kinases / metabolism*

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • Caspase Inhibitors
  • Culture Media, Serum-Free
  • Enzyme Precursors
  • Recombinant Proteins
  • lactacystin
  • Carbon Tetrachloride
  • Ribosomal Protein S6 Kinases
  • Caspases
  • Acetylcysteine