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PEA3 cooperates with c-Jun in regulation of HER2/neu transcription

Koshi Matsui1, Kazuhito Sugimori, Hiraku Motomura

  • 1Second Department of Surgery, University of Toyama, Toyama 930-0194, Japan.

Oncology Reports
|June 21, 2006
PubMed

Insights

Polyomavirus enhancer activator 3 (PEA3) and c-Jun cooperate to enhance HER2/neu gene transcription in breast tumors. This synergistic action, involving the coactivator p300, offers insights into HER2/neu overexpression mechanisms.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • HER2/neu overexpression is common in aggressive breast tumors.
  • Polyomavirus enhancer activator 3 (PEA3) expression is elevated in these tumors.
  • The precise role of PEA3 in HER2/neu transcriptional activation is not fully understood.

Purpose of the Study:

  • To investigate the relationship between HER2/neu transcriptional activation and PEA3.
  • To explore the cooperative role of PEA3 with c-Jun in regulating HER2/neu.
  • To elucidate the involvement of coactivator p300 in this regulatory pathway.

Main Methods:

  • Deletion and mutation analysis of the PEA3 binding site on the HER2/neu promoter.
  • Luciferase reporter assays to measure promoter activity.
  • Two-hybrid system to assess protein-protein interactions.
  • Cotransfection experiments in MCF7 cells with PEA3, c-Jun, and p300.

Main Results:

  • Disruption of the PEA3 binding site significantly reduced HER2/neu promoter activity.
  • PEA3 and c-Jun individually showed weak enhancement, but synergistically increased HER2/neu transcription.
  • c-Jun specifically enhanced the transcriptional activity of PEA3.
  • Coexpression of PEA3, c-Jun, and p300 led to a 20-fold increase in HER2/neu transcription.
  • Dominant-negative p300 repressed PEA3 and c-Jun-mediated HER2/neu transcription.

Conclusions:

  • PEA3 and c-Jun act synergistically to stimulate HER2/neu gene transcription.
  • The coactivator p300 is essential for this synergistic transcriptional activation.
  • These findings provide a molecular mechanism for PEA3's role in HER2/neu overexpression in breast cancer.

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