PT  - JOURNAL ARTICLE
AU  - Shuo Wei
AU  - Hsiao-Ching Chuang
AU  - Wan-Chi Tsai
AU  - Hsiao-Ching Yang
AU  - Shiuh-Rong Ho
AU  - Andrew J. Paterson
AU  - Samuel K. Kulp
AU  - Ching-Shih Chen
TI  - Thiazolidinediones Mimic Glucose Starvation in Facilitating Sp1 Degradation through the Up-Regulation of β-Transducin Repeat-Containing Protein
AID  - 10.1124/mol.109.055376
DP  - 2009 Jul 01
TA  - Molecular Pharmacology
PG  - 47--57
VI  - 76
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/76/1/47.short
4100  - http://molpharm.aspetjournals.org/content/76/1/47.full
SO  - Mol Pharmacol2009 Jul 01; 76
AB  - This study investigated the mechanism by which the transcription factor Sp1 is degraded in prostate cancer cells. We recently developed a thiazolidinedione derivative, (Z)-5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(1-methylcyclohexyl)-thiazolidine-2,4-dione (OSU-CG12), that induces Sp1 degradation in a manner paralleling that of glucose starvation. Based on our finding that thiazolidinediones suppress β-catenin and cyclin D1 by up-regulating the E3 ligase SCFβ-TrCP, we hypothesized that β-transducin repeat-containing protein (β-TrCP) targets Sp1 for proteasomal degradation in response to glucose starvation or OSU-CG12. Here we show that either treatment of LNCaP cells increased specific binding of Sp1 with β-TrCP. This direct binding was confirmed by in vitro pull-down analysis with bacterially expressed β-TrCP. Although ectopic expression of β-TrCP enhanced the ability of OSU-CG12 to facilitate Sp1 degradation, suppression of endogenous β-TrCP function by a dominant-negative mutant or small interfering RNA-mediated knockdown blocked OSU-CG12-facilitated Sp1 ubiquitination and/or degradation. Sp1 contains a C-terminal conventional DSG destruction box (727DSGAGS732) that mediates β-TrCP recognition and encompasses a glycogen synthase kinase 3β (GSK3β) phosphorylation motif (SXXXS). Pharmacological and molecular genetic approaches and mutational analyses indicate that extracellular signal-regulated kinase-mediated phosphorylation of Thr739 and GSK3β-mediated phosphorylation of Ser728 and Ser732 were critical for Sp1 degradation. The ability of OSU-CG12 to mimic glucose starvation to activate β-TrCP-mediated Sp1 degradation has translational potential to foster novel strategies for cancer therapy.