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Coactivator PC4 mediates AP-2 transcriptional activity and suppresses ras-induced transformation dependent on AP-2

P Kannan1, M A Tainsky

  • 1MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 44109, USA.

Molecular and Cellular Biology
|December 22, 1998
PubMed

Insights

Ras oncogene transformation of teratocarcinoma cells inhibits AP-2 activity. Restoring this activity with PC4 coactivator suppresses tumor growth, revealing a novel mechanism of oncogenic transformation.

Area of Science:

  • Molecular Biology
  • Oncology
  • Transcriptional Regulation

Background:

  • Ras oncogene transformation of PA-1 human teratocarcinoma cells leads to abundant AP-2 mRNA but low AP-2 transcriptional activity.
  • Overexpression of AP-2 in non-tumorigenic PA-1 variants inhibits AP-2 activity and induces tumorigenicity, suggesting a novel inhibition mechanism involving coactivator sequestration.

Purpose of the Study:

  • To investigate the role of transcriptional coactivators in ras-mediated cellular transformation.
  • To identify specific coactivators involved in regulating AP-2 activity in teratocarcinoma cells.

Main Methods:

  • Utilized ras-transformed PA-1 cells and their non-tumorigenic variants.
  • Investigated the function of PC4 as a potential coactivator for AP-2.
  • Assessed the impact of PC4 re-expression on cell growth, anchorage-independent growth, and tumor formation in nude mice.

Main Results:

  • PC4 was identified as a positive coactivator of AP-2, capable of restoring AP-2 activity in ras-transformed PA-1 cells.
  • Stable transfection and expression of PC4 cDNA in ras-transformed cells resulted in diminished growth rate and loss of anchorage-independent growth.
  • PC4-expressing cells were unable to induce tumor formation in nude mice, indicating a tumor-suppressive effect.

Conclusions:

  • Transcriptional coactivators, such as PC4, can exert growth-suppressive effects on cancer cells, functioning similarly to tumor suppressors.
  • Ras oncogenes and oncogenic transcription factors can induce cellular transformation by directly impacting the transcription machinery, rather than solely through specific gene expression programs.

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