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Research ArticleArticle

Thiazolidinediones Mimic Glucose Starvation in Facilitating Sp1 Degradation through the Up-Regulation of β-Transducin Repeat-Containing Protein

Shuo Wei, Hsiao-Ching Chuang, Wan-Chi Tsai, Hsiao-Ching Yang, Shiuh-Rong Ho, Andrew J. Paterson, Samuel K. Kulp and Ching-Shih Chen
Molecular Pharmacology July 2009, 76 (1) 47-57; DOI: https://doi.org/10.1124/mol.109.055376
Shuo Wei
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Hsiao-Ching Chuang
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Wan-Chi Tsai
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Hsiao-Ching Yang
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Shiuh-Rong Ho
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Andrew J. Paterson
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Samuel K. Kulp
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Ching-Shih Chen
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Abstract

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.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grant CA112250] and the Department of Defense Prostate Cancer Research Program [Grant W81XWH-09-1-0198].

  • ABBREVIATIONS: PPARγ, peroxisome proliferator-activated receptor-γ; AR, androgen receptor; β-TrCP, β-transducin repeat-containing protein; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase 3β; GST, glutathione transferase; HA, hemagglutinin; JNK, Jun NH2-terminal kinase; MEK, mitogen-activated protein kinase kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; WT, wild-type; ΔF-β-TrCP, F-box-deleted β-transducin repeat-containing protein; IP, immunoprecipitation; IB, immunoblotting; HA-UB, hemagglutinin-ubiquitin; Hsp90, heat shock protein 90; MAP, mitogen-activated protein; STE buffer, STE buffer, Tris/NaCl/EDTA/dithiothreitol/phenylmethylsulfonyl fluoride; M-PER, mammalian protein extraction reagent; PCR, polymerase chain reaction; DMSO, dimethyl sulfoxide; IKKα,IκB kinase α; siRNA, small interfering RNA; FBS, fetal bovine serum; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; PD98059, 2′-amino-3′-methoxyflavone; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; SB216763, 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3yl)-1H-pyrrole-2,5-dione; SP600125, anthra[1,9-c,d]pyrazol-6(2H)-one; PD169316, 4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)1H-imidazole; OSU-CG12, (Z)-5-(4-hydroxy-3-trifluoromethylbenzylidene)-3-(1-methylcyclohexyl)thiazolidine-2,4-dione.

    • Accepted April 16, 2009.
    • Received February 7, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (1)
Molecular Pharmacology
Vol. 76, Issue 1
1 Jul 2009
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Research ArticleArticle

Thiazolidinediones Mimic Glucose Starvation in Facilitating Sp1 Degradation through the Up-Regulation of β-Transducin Repeat-Containing Protein

Shuo Wei, Hsiao-Ching Chuang, Wan-Chi Tsai, Hsiao-Ching Yang, Shiuh-Rong Ho, Andrew J. Paterson, Samuel K. Kulp and Ching-Shih Chen
Molecular Pharmacology July 1, 2009, 76 (1) 47-57; DOI: https://doi.org/10.1124/mol.109.055376

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Research ArticleArticle

Thiazolidinediones Mimic Glucose Starvation in Facilitating Sp1 Degradation through the Up-Regulation of β-Transducin Repeat-Containing Protein

Shuo Wei, Hsiao-Ching Chuang, Wan-Chi Tsai, Hsiao-Ching Yang, Shiuh-Rong Ho, Andrew J. Paterson, Samuel K. Kulp and Ching-Shih Chen
Molecular Pharmacology July 1, 2009, 76 (1) 47-57; DOI: https://doi.org/10.1124/mol.109.055376
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