TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation

Nat Cell Biol. 2001 Aug;3(8):708-14. doi: 10.1038/35087019.

Abstract

Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that has a principal role in growth control through both its cytostatic effect on many different epithelial cell types and its ability to induce programmed cell death in a variety of other cell types. Here we have used a screen for proteins that interact physically with the cytoplasmic domain of the type II TGF-beta receptor to isolate the gene encoding Daxx - a protein associated with the Fas receptor that mediates activation of Jun amino-terminal kinase (JNK) and programmed cell death induced by Fas. The carboxy-terminal portion of Daxx functions as a dominant-negative inhibitor of TGF-beta-induced apoptosis in B-cell lymphomas, and antisense oligonucleotides to Daxx inhibit TGF-beta-induced apoptosis in mouse hepatocytes. Furthermore, Daxx is involved in mediating JNK activation by TGF-beta. Our findings associate Daxx directly with the TGF-beta apoptotic-signalling pathway, and make a biochemical connection between the receptors for TGF-beta and the apoptotic machinery.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • COS Cells / cytology
  • COS Cells / drug effects
  • COS Cells / metabolism
  • Carrier Proteins / drug effects
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Compartmentation / drug effects
  • Cell Compartmentation / genetics
  • Cell Division / drug effects
  • Cell Division / genetics*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / genetics*
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Chaperones
  • Nuclear Proteins*
  • Oligonucleotides, Antisense / pharmacology
  • Protein Structure, Tertiary / drug effects
  • Protein Structure, Tertiary / genetics
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / genetics
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Two-Hybrid System Techniques
  • Yeasts / drug effects
  • Yeasts / genetics
  • Yeasts / metabolism
  • fas Receptor / drug effects
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DAXX protein, human
  • Daxx protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • fas Receptor
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • Receptor, Transforming Growth Factor-beta Type II