Peroxisome Proliferator-activated Receptor γ Activation Can Regulate β-Catenin Levels via a Proteasome-mediated and Adenomatous Polyposis Coli-independent Pathway*

The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) belongs to the family of nuclear hormone receptors and consists of two isotypes, PPARγ1 and PPARγ2. Our earlier studies have shown that troglitazone (TZD)-mediated activation of PPARγ2 in hepatocytes inhibits growth and attenuates cyclin D1 transcription via modulating CREB levels. Because this process of growth inhibition was also associated with an inhibition of β-catenin expression at a post-translational level, our aim was to elucidate the mechanism involved. β-Catenin is a multifunctional protein, which can regulate cell-cell adhesion by interacting with E-cadherin and other cellular processes via regulating target gene transcription in association with TCF/LEF transcription factors. Two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways, one involving glycogen synthase kinase 3β (GSK3β) and the other involving p53-Siah-1, degrade excess β-catenin in normal cells. Our immunofluorescence and Western blot studies indicated a TZD-dependent decrease in cytoplasmic and membrane-bound β-catenin, indicating no increase in its membrane translocation. This was associated with a reduction in E-cadherin expression. PPARγ2 activation inhibited GSK3β kinase activity, and pharmacological inhibition of GSK3β activity was unable to restore β-catenin expression following PPARγ2 activation. Additionally, this β-catenin degradation pathway was operative in cells, with inactivating mutations of both APC and p53. Inhibition of the proteasomal pathway inhibited PPARγ2-mediated degradation of β-catenin, and incubation with TZD increased ubiquitination of β-catenin. We conclude that PPARγ2-mediated suppression of β-catenin levels involves a novel APC/GSK3β/p53-independent ubiquitination-mediated proteasomal degradation pathway.

• Publication year

  2004

• Venue

  Journal of Biological Chemistry

• Publication date

  2004-08-20

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M403143200
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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