Thiazolidinediones Modulate the Expression of β-Catenin and Other Cell-Cycle Regulatory Proteins by Targeting the F-Box Proteins of Skp1-Cul1-F-box Protein E3 Ubiquitin Ligase Independently of Peroxisome Proliferator-Activated Receptor γ
Resource
Molecular Pharmacology 72 (3): 725-733
Journal
Molecular Pharmacology
Journal Volume
72
Journal Issue
3
Pages
725-733
Date Issued
2007
Date
2007
Author(s)
Abstract
Considering the role of aberrant β-catenin signaling in tumorigenesis, we investigated the mechanism by which the peroxisome proliferator-activated receptor γ (PPARγ) agonist troglitazone facilitated β-catenin down-regulation. We demonstrate that troglitazone and its more potent PPARγ-inactive analogs Δ2TG and STG28 mediated the proteasomal degradation of β-catenin in prostate cancer cells by up-regulating the expression of β-transducin repeat-containing protein (β-TrCP), an F-box component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase. Evidence indicates that although small interfering RNA-mediated β-TrCP knockdown protected cells against STG28-facilitated β-catenin ablation, ectopic β-TrCP expression enhanced the degradation. The involvement of β-TrCP in β-catenin degradation was also corroborated by the pull-down analysis and the concurrent down-regulation of known β-TrCP substrates examined, including Wee1, Iκβα, cdc25A, and nuclear factor-κB/p105. Furthermore, glycogen synthase kinase-3β represented a key regulator in the effect of these thiazolidinedione derivatives on β-catenin proteolysis even though these agents increased its phosphorylation level. It is noteworthy that this drug-induced β-TrCP up-regulation was accompanied by the concomitant down-regulation of Skp2 and Fbw7, thereby affecting many of the target proteins of these two F-box proteins (such as p27 and cyclin E). As a consequence, the ability of troglitazone to target these F-box proteins provides a molecular basis to account for its reported effect on modulating the expression of aforementioned cell-cycle regulatory proteins. Despite this complicated mode of pharmacological actions, normal prostate epithelial cells, relative to LNCaP cells, were less susceptible to the effects of STG28 on modulating the expression of β-catenin and β-TrCP, suggesting the translation potential of using STG28 as a scaffold to develop more potent chemopreventive agents. Copyright ? 2007 The American Society for Pharmacology and Experimental Therapeutics.
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Other Subjects
2,4 thiazolidinedione derivative; beta catenin; beta transducin repeat containing protein; cullin; Cullin 1; cyclin E; F box protein; glycogen synthase kinase 3beta; I kappa B kinase alpha; I kappa B kinase beta; immunoglobulin enhancer binding protein; nuclear protein; peroxisome proliferator activated receptor gamma; proteasome; protein p105; protein p27; protein tyrosine phosphatase; protein wee1; S phase kinase associated protein; S phase kinase associated protein 2; small interfering RNA; stg 28; troglitazone; ubiquitin protein ligase E3; unclassified drug; article; cell cycle regulation; controlled study; down regulation; drug mechanism; drug structure; gene repression; gene targeting; human; human cell; pleiotropy; priority journal; prostate cancer; protein degradation; protein expression; protein phosphorylation; upregulation; beta Catenin; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Cullin Proteins; F-Box Proteins; Formazans; Glutathione Transferase; Humans; Male; PPAR gamma; Prostatic Neoplasms; Recombinant Fusion Proteins; RNA Interference; S-Phase Kinase-Associated Proteins; Tetrazolium Salts; Thiazolidinediones; Ubiquitin-Protein Ligases
Type
journal article
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