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Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc

Qing Wang1, Yan Zhang, Hsin-Sheng Yang

  • 1Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.

Biochimica Et Biophysica Acta
|July 18, 2012
PubMed

Insights

Programmed cell death 4 (Pdcd4) down-regulation activates MAP kinase kinase kinase kinase 1 (MAP4K1) and AP-1 signaling via c-Myc. This uncovers a mechanism linking Pdcd4, β-catenin/Tcf, and tumor cell invasion.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • Programmed cell death 4 (Pdcd4) functions as a tumor suppressor, often downregulated in cancers.
  • The precise mechanisms by which Pdcd4 inhibits tumor progression are under investigation.

Purpose of the Study:

  • To elucidate the molecular pathways regulated by Pdcd4, specifically its role in cancer cell invasion.
  • To investigate the relationship between Pdcd4, MAP4K1, c-Myc, and AP-1 signaling.

Main Methods:

  • Cell culture and manipulation (knockdown and overexpression).
  • Analysis of gene expression and protein phosphorylation (Western blotting, reporter assays).
  • Chromatin immunoprecipitation (ChIP) to assess protein-DNA interactions.

Main Results:

  • Pdcd4 knockdown increased MAP kinase kinase kinase kinase 1 (MAP4K1) expression and c-Jun phosphorylation.
  • c-Myc directly binds to the MAP4K1 promoter and regulates its activity.
  • Activation of β-catenin/Tcf signaling in Pdcd4-deficient cells upregulates MAP4K1 and AP-1 activity through c-Myc.

Conclusions:

  • Pdcd4 suppresses tumor cell invasion by inhibiting the β-catenin/Tcf-c-Myc-MAP4K1-AP-1 signaling axis.
  • This study reveals a detailed mechanism connecting Pdcd4 function to key cancer-related signaling pathways.

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