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Differentiation-inducing factor-1 suppresses gene expression of cyclin D1 in tumor cells

Tania Yasmin1, Fumi Takahashi-Yanaga, Jun Mori

  • 1Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Biochemical and Biophysical Research Communications
|October 26, 2005
PubMed

Insights

Differentiation-inducing factor-1 (DIF-1) inhibits tumor cell proliferation by reducing cyclin D1 expression. This occurs through the Wnt/beta-catenin signaling pathway, involving glycogen synthase kinase-3beta (GSK-3beta) activation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor cell proliferation is a hallmark of cancer.
  • Understanding the molecular mechanisms regulating cell proliferation is crucial for developing targeted therapies.
  • The Wnt/beta-catenin signaling pathway plays a significant role in cell growth and cancer development.

Purpose of the Study:

  • To elucidate the mechanism by which differentiation-inducing factor-1 (DIF-1) inhibits tumor cell proliferation.
  • To investigate the effect of DIF-1 on cyclin D1 gene expression and its regulatory pathways.

Main Methods:

  • Examined the effect of DIF-1 on cyclin D1 mRNA expression in HeLa and squamous cell carcinoma cells.
  • Assessed beta-catenin levels following DIF-1 treatment.
  • Investigated the role of glycogen synthase kinase-3beta (GSK-3beta) in DIF-1-mediated effects.
  • Utilized T-cell factor (TCF)/lymphoid enhancer factor (LEF) reporter plasmids and a human cyclin D1 promoter-driven reporter gene assay.

Main Results:

  • DIF-1 significantly reduced cyclin D1 mRNA expression and beta-catenin levels in cancer cells.
  • DIF-1 activated GSK-3beta, and GSK-3beta inhibition attenuated DIF-1-induced beta-catenin degradation.
  • DIF-1 suppressed TCF/LEF reporter activity and activity of a reporter gene driven by the human cyclin D1 promoter.
  • Deletion of the TCF/LEF consensus site in the cyclin D1 promoter abolished the effect of DIF-1.

Conclusions:

  • DIF-1 inhibits tumor cell proliferation by suppressing Wnt/beta-catenin signaling.
  • The mechanism involves GSK-3beta activation leading to beta-catenin degradation and reduced cyclin D1 promoter activity.
  • DIF-1 represents a potential therapeutic agent targeting aberrant Wnt/beta-catenin signaling in cancer.

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