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

R Perlman1, W P Schiemann, M W Brooks

  • 1Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

Nature Cell Biology
|August 3, 2001
PubMed

Insights

This study identifies Daxx as a key protein in transforming growth factor-beta (TGF-beta) signaling. Daxx mediates TGF-beta-induced apoptosis and Jun amino-terminal kinase (JNK) activation, linking TGF-beta receptors to cell death pathways.

Area of Science:

  • Cell biology
  • Molecular biology
  • Cancer research

Background:

  • Transforming growth factor-beta (TGF-beta) is a critical regulator of cell growth and apoptosis.
  • The TGF-beta signaling pathway plays a significant role in controlling cell proliferation and programmed cell death.
  • Understanding the molecular mechanisms underlying TGF-beta-induced apoptosis is crucial for cancer research.

Purpose of the Study:

  • To identify proteins that physically interact with the cytoplasmic domain of the type II TGF-beta receptor.
  • To investigate the role of the identified protein, Daxx, in TGF-beta signaling and apoptosis.
  • To establish a biochemical link between TGF-beta receptors and the apoptotic machinery.

Main Methods:

  • Protein-protein interaction screening using the cytoplasmic domain of the type II TGF-beta receptor.
  • Identification of Daxx, a protein previously associated with the Fas receptor.
  • Functional assays including dominant-negative inhibition and antisense oligonucleotide treatment.
  • Analysis of Jun amino-terminal kinase (JNK) activation.

Main Results:

  • Daxx was identified as a protein interacting with the type II TGF-beta receptor.
  • The carboxy-terminal portion of Daxx inhibited TGF-beta-induced apoptosis in B-cell lymphomas.
  • Antisense oligonucleotides targeting Daxx reduced TGF-beta-induced apoptosis in mouse hepatocytes.
  • Daxx was found to mediate JNK activation induced by TGF-beta.

Conclusions:

  • Daxx is directly involved in the TGF-beta apoptotic signaling pathway.
  • Daxx acts as a crucial mediator of TGF-beta-induced programmed cell death.
  • These findings establish a direct biochemical connection between TGF-beta receptors and the cellular apoptotic machinery.

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