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Peroxisome proliferator-activated receptor gamma activation modulates cyclin D1 transcription via

Chandan Sharma1, Anamika Pradeep, Richard G Pestell

  • 1Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA.

The Journal of Biological Chemistry
|February 7, 2004
PubMed

Insights

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits cyclin D1 transcription in hepatocytes. This occurs through a cAMP-response element-binding protein (CREB)-dependent pathway, independent of beta-catenin, leading to growth arrest.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARgamma) activation by specific ligands inhibits carcinoma cell growth.
  • PPARgamma plays a role in cell proliferation and differentiation.
  • Cyclin D1 is a key regulator of cell cycle progression.

Purpose of the Study:

  • To investigate the mechanism by which PPARgamma2 activation modulates cyclin D1 transcription in mouse hepatocytes.
  • To determine the role of beta-catenin and cAMP-response element-binding protein (CREB) in PPARgamma2-mediated regulation of cyclin D1.

Main Methods:

  • Utilized stable PPARgamma-overexpressing AML-12 mouse hepatocyte cell lines.
  • Treated cells with troglitazone (TZD), a PPARgamma ligand.
  • Assessed expression of proliferating cell nuclear antigen, cyclin D1, and beta-catenin.
  • Measured cyclin D1 promoter activity, CREB activity, and cAMP-response element-mediated transcription.
  • Overexpressed wild-type/mutant beta-catenin and CREB.

Main Results:

  • TZD treatment activated PPARgamma2, causing growth arrest and down-regulating cyclin D1 and beta-catenin expression.
  • PPARgamma2 activation attenuated cyclin D1 promoter activity, indicating transcriptional regulation.
  • Overexpression of beta-catenin did not rescue cyclin D1 suppression, while CREB overexpression antagonized it.
  • TZD inhibited CREB activity and cAMP-response element-mediated transcription.
  • Okadaic acid pretreatment partially reversed TZD-mediated inhibition of CREB and cyclin D1 transcription.

Conclusions:

  • PPARgamma2 activation inhibits cyclin D1 transcription in hepatocytes.
  • This inhibition is mediated by a CREB-dependent pathway.
  • The mechanism is independent of beta-catenin.
  • PPARgamma2 activation represents a potential therapeutic target for controlling cell proliferation.

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