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

Abstract

The transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) belongs to the family of nuclear hormone receptors and consists of two isotypes, PPAR␥1 and PPAR␥2. Our earlier studies have shown that troglitazone (TZD)-mediated activation of PPAR␥2 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 ␤-catenin expression at a post-translational level, our aim was to elucidate the mechanism involved. ␤-Catenin is a multifunctional protein, which can regulate cell-cell adhesion by interacting with Ecadherin 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 3␤ (GSK3␤) and the other involving p53-Siah-1, degrade excess ␤-catenin in normal cells. Our immunofluorescence and Western blot studies indicated a TZD-dependent decrease in cytoplasmic and membrane-bound ␤-catenin, indicating no increase in its membrane translocation. This was associated with a reduction in E-cadherin expression. PPAR␥2 activation inhibited GSK3␤ kinase activity, and pharmacological inhibition of GSK3␤ activity was unable to restore ␤-catenin expression following PPAR␥2 activation. Additionally, this ␤-catenin degradation pathway was operative in cells, with inactivating mutations of both APC and p53. Inhibition of the proteasomal pathway inhibited PPAR␥2-mediated degradation of ␤-catenin, and incubation with TZD increased ubiquitination of ␤-catenin. We conclude that PPAR␥2-mediated suppression of ␤-catenin levels involves a novel APC/ GSK3␤/p53-independent ubiquitination-mediated proteasomal degradation pathway.

Repression of β-catenin function in malignant cells by nonsteroidal antiinflammatory drugs

“…Not only NSAIDs, but also the PPAR-␥ ligand troglitazone, and the RXR-␣ ligand 9-cis-retinoic acid, antagonized ␤-catenindependent reporter gene activity (58,59). However, antagonism of ␤-catenin by R-etodolac could not be attributed to PPAR-␥ or RXR-␣ activation.…”

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

“…However, the upregulation of Wnt/beta-catenin signaling observed in ALS suggests that PPAR gamma might be downregulated due to the fact that these two systems generally operate in the opposite way [1][2][3]5]. Neuroinflammation is a common pathological feature in NDs, particularly in ALS.…”

“…The thiazolidinedione PPAR gamma agonists (TZDs), troglitazone, rosiglitazone and pioglitazone, and a non-thiazolidinedione PPAR gamma activator, GW1929, inhibit the beta-catenininduced transcription in a PPAR gamma-dependent fashion [1][2][3]5]. Troglitazone-mediated activation of PPAR gamma is associated with an inhibition of beta-catenin at a post-transcriptional level.…”

“…Treatment with PPAR gamma agonists decreases mRNA and protein levels of betacatenin in 3T3L1 adipocytes [1]. TZDs induce a reduction in the levels of cytoplasmic betacatenin in hepatocytes [3]. PPAR gamma suppresses Wnt/beta-catenin pathway during adipogenesis [2].…”

“…Two major systems play a key role in the pathophysiology of NDs, i.e., the canonical Wnt/betacatenin pathway and PPAR gamma. Several studies have demonstrated the opposite interaction between the canonical Wnt/beta-catenin pathway and the PPAR gamma [1][2][3][4][5][6][7]. It has recently been shown that certain NDs can be divided into two classes [8]: on one hand, NDs in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregulated.…”