Axin-induced apoptosis depends on the extent of its JNK activation and its ability to down-regulate beta-catenin levels

Biochem Biophys Res Commun. 2000 May 27;272(1):144-50. doi: 10.1006/bbrc.2000.2751.

Abstract

Axin is a multidomain protein that coordinates a variety of critical factors in Wnt signaling and JNK activation. In this study, we found that overexpression of Axin leads to apoptosis in several cell lines. A mutant Axin (Axin-deltaMID) that does not contain the MEKK1-interacting domain and is not capable of activating JNK, has less apoptotic effect. Together with the observations that dominant-negative forms of MEKK1 and JNK1 can attenuate Axin-induced apoptosis, we suggest that JNK activation is required for Axin-mediated apoptosis. Wild-type Axin proteins that can lead to destabilization of beta-catenin are more effective at causing cell death than those constructs (Axin-deltaGSK/beta-cat, Axin-deltaRGS/GSK/beta-cat) that are defective in regulation of beta-catenin but still fully capable of JNK activation. Furthermore, enhanced beta-catenin signaling by coexpression of beta-catenin or PP2C alpha attenuate cell death. Taken together, we suggest that the ability of Axin to induce apoptosis is determined by its ability to activate JNK and destabilize beta-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Axin Protein
  • CHO Cells
  • Caspase Inhibitors
  • Cricetinae
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Down-Regulation
  • Enzyme Activation
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation
  • Oligopeptides / pharmacology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Repressor Proteins*
  • Signal Transduction
  • Trans-Activators*
  • beta Catenin

Substances

  • Axin Protein
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Cytoskeletal Proteins
  • Oligopeptides
  • Proteins
  • Repressor Proteins
  • Trans-Activators
  • beta Catenin
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases