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Methods to Discover Alternative Promoter Usage and Transcriptional Regulation of Murine Bcrp1
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Tumor promoter-induced ornithine decarboxylase gene expression occurs independently of AP-1 activation

A P Jansen1, N H Colburn, A K Verma

  • 1Department of Human Oncology, Medical School, University of Wisconsin, Madison, Wisconsin, WI 53792, USA.

Oncogene
|October 19, 1999
PubMed

Insights

12-O-tetradecanoylphorbol-13-acetate (TPA) induces ornithine decarboxylase (ODC) gene expression and activity independently of Activator protein 1 (AP-1) transactivation. This suggests two distinct pathways are involved in TPA-induced skin tumor promotion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Activator protein 1 (AP-1) transactivation and ornithine decarboxylase (ODC) activity are key downstream effectors in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tumor promotion.
  • Previous research indicates that inhibiting either AP-1 or ODC suppresses tumor promoter-induced transformation.

Purpose of the Study:

  • To investigate whether TPA-induced ODC gene expression and activity are independent of AP-1 transactivation using the JB6 mouse epidermal cell system.
  • To elucidate the relationship between AP-1 and ODC in the context of TPA-induced cell transformation.

Main Methods:

  • Utilized JB6 mouse epidermal cell lines (P+ and P-) with stable expression of dominant-negative c-jun or vector control.
  • Assessed TPA-induced ODC gene expression, ODC activity, and AP-1-dependent transcription.
  • Employed alpha-difluoromethylornithine (DFMO), an irreversible ODC inhibitor, to evaluate its effect on TPA-induced ODC activity and anchorage-independent growth.

Main Results:

  • TPA-induced ODC gene expression and activity were unaffected by dominant-negative c-jun, despite inhibited AP-1 transcription.
  • Transformation-insensitive JB6 (P-) cells lacking TPA-inducible c-jun also showed similar ODC activity induction by TPA.
  • DFMO attenuated both TPA-induced ODC activity and anchorage-independent growth at an equivalent IC50, without inhibiting AP-1 transactivation.

Conclusions:

  • TPA-induced ODC gene expression and activity are independent of AP-1 transactivation.
  • The findings support a model with at least two distinct pathways to TPA-induced cell transformation: one involving AP-1 and another involving ODC.
  • Each pathway is necessary but not sufficient for TPA-induced transformation, highlighting the complex signaling network in skin carcinogenesis.

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