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The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through

Yosuke Funato1, Tatsuo Michiue, Makoto Asashima

  • 1Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

Nature Cell Biology
|April 11, 2006
PubMed

Insights

Nucleoredoxin (NRX) interacts with Dishevelled (Dvl), regulating the Wnt-beta-catenin pathway. NRX suppresses this pathway, while its absence activates it, impacting cell proliferation and oncogenicity, revealing a link to redox signaling.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Dishevelled (Dvl) is a key transducer in the Wnt signaling pathway, mediating signal transmission from Frizzled receptors to downstream effectors.
  • Stabilization of beta-catenin and subsequent activation of TCF/LEF transcription factors are critical outcomes of Wnt pathway activation.
  • The precise molecular mechanisms governing Dvl function and its regulation remain incompletely understood.

Purpose of the Study:

  • To investigate the interaction of nucleoredoxin (NRX) with Dishevelled (Dvl) and elucidate its role in Wnt-beta-catenin signaling.
  • To determine the impact of NRX modulation on Wnt pathway activity, cell proliferation, and oncogenicity.
  • To explore the potential connection between redox signaling and the Wnt-beta-catenin pathway.

Main Methods:

  • Co-immunoprecipitation assays to detect NRX-Dvl interaction.
  • Overexpression and RNA-interference (RNAi) studies to modulate NRX levels.
  • Western blotting and reporter assays to assess Wnt pathway activation (TCF/LEF activity).
  • Cell proliferation and oncogenicity assays.
  • Stimulation with hydrogen peroxide (H2O2) to investigate redox effects.

Main Results:

  • Nucleoredoxin (NRX), a thioredoxin family protein, was found to interact with Dishevelled (Dvl).
  • Overexpression of NRX suppressed the Wnt-beta-catenin pathway, whereas NRX ablation via RNAi activated TCF/LEF signaling, accelerated cell proliferation, and enhanced oncogenicity.
  • Redox signaling, specifically H2O2 stimulation, activated TCF/LEF independently of extracellular Wnts, an effect impaired by NRX RNAi.
  • Hydrogen peroxide treatment disrupted the association between Dvl and NRX, indicating redox-sensitive regulation.

Conclusions:

  • Nucleoredoxin (NRX) acts as a negative regulator of the Wnt-beta-catenin pathway through its interaction with Dishevelled (Dvl).
  • The Wnt-beta-catenin pathway is subject to redox-dependent regulation, influenced by the redox-sensitive association of NRX with Dvl.
  • These findings reveal a novel link between redox signaling and Wnt pathway activation, with implications for understanding cell proliferation and oncogenesis.

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