RT Journal Article
SR Electronic
T1 Thiazolidinediones Mimic Glucose Starvation in Facilitating Sp1 Degradation through the Up-Regulation of β-Transducin Repeat-Containing Protein
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 47
OP 57
DO 10.1124/mol.109.055376
VO 76
IS 1
A1 Shuo Wei
A1 Hsiao-Ching Chuang
A1 Wan-Chi Tsai
A1 Hsiao-Ching Yang
A1 Shiuh-Rong Ho
A1 Andrew J. Paterson
A1 Samuel K. Kulp
A1 Ching-Shih Chen
YR 2009
UL http://molpharm.aspetjournals.org/content/76/1/47.abstract
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.