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Raf 1 represses expression of the tight junction protein occludin via activation of the zinc-finger transcription

Z Wang1, P Wade, K J Mandell

  • 1Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA 30322, USA.

Oncogene
|August 23, 2006
PubMed

Insights

Oncogenic Raf 1 downregulates occludin, a tight junction protein, by increasing Slug. Slug directly binds the occludin promoter, mediating Raf 1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Dysregulation of tight junction (TJ) proteins is linked to epithelial cancers.
  • The precise mechanisms driving TJ protein involvement in epithelial transformation remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which oncogenic Raf 1 regulates occludin expression.
  • To investigate the role of transcriptional repressors in Raf 1-mediated occludin downregulation.

Main Methods:

  • Utilized Pa4 epithelial cells expressing oncogenic Raf 1.
  • Performed reporter assays to assess occludin promoter activity.
  • Employed small interfering RNA (siRNA) for gene silencing.
  • Conducted chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis.

Main Results:

  • Raf 1 inhibited occludin transcription by repressing its promoter.
  • Raf 1 upregulated the transcriptional repressor Slug, but not Snail.
  • Slug overexpression mimicked Raf 1's effect on occludin; Slug depletion abrogated it.
  • Slug directly bound to an E-box in the occludin promoter.

Conclusions:

  • Slug mediates Raf 1-induced transcriptional repression of occludin.
  • This mechanism contributes to oncogenic transformation and epithelial to mesenchymal transition (EMT).

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