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Molecular Pharmacology

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Research ArticleArticle

Role of p90 Ribosomal S6-Kinase-1 in Oltipraz-Induced Specific Phosphorylation of CCAAT/Enhancer Binding Protein-β for GSTA2 Gene Transactivation

Seung Jin Lee and Sang Geon Kim
Molecular Pharmacology January 2006, 69 (1) 385-396; DOI: https://doi.org/10.1124/mol.105.018465
Seung Jin Lee
National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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Sang Geon Kim
National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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Abstract

Oltipraz, which has been extensively studied as a cancer chemopreventive agent, promotes phosphatidylinositol 3-kinase-mediated activation of CCAAT/enhancer binding protein-β (C/EBPβ). Activated p90 ribosomal S6-kinase-1 (RSK1) phosphorylates major transcription factors, including C/EBPβ. This study examined whether oltipraz induces phosphorylation of C/EBPβ at specific residues, and if so, whether RSK1 regulates C/EBPβ phosphorylation by oltipraz for the GSTA2 gene transactivation. Subcellular fractionation and immunoblot analyses revealed that oltipraz treatment increased the level of C/EBPβ phosphorylated at Ser105 in the cytoplasm, which translocated to the nucleus for DNA binding in rat H4IIE cells. Immunoprecipitation-immunoblot, chromatin-immunoprecipitation, and specific mutation analyses revealed that Ser105-phosphorylated C/EBPβ recruited the cAMP response element-binding protein binding protein for histone acetylation and transactivation of the GSTA2 gene. The role of RSK1 in Ser105-phosphorylation of C/EBPβ by oltipraz and its gene transactivation was evidenced by transfection experiments with dominant-negative mutants of RSK1. In mouse Hepa1c1c, human HepG2 cells, and rat primary hepatocytes, oltipraz induced phosphorylation of C/EBPβ at Thr217, Thr266, and Ser105, respectively, via RSK1. The experiment using small-interference RNA of RSK1 confirmed the essential role of RSK1 in the gene expression. Inhibition of PI3-kinase activity prevented oltipraz-inducible Ser105-phosphorylation of rat C/EBPβ. Oltipraz treatment led to increases in the catalytic activity and nuclear translocation of RSK1, which was abrogated by PI3-kinase inhibition. In summary, oltipraz induces the phosphorylation of rat C/EBPβ at Ser105 (functionally analogous Thr217/266 in mouse and human forms) in hepatocytes, which results in cAMP response element-binding protein-binding protein (CBP) recruitment for the GSTA2 gene transactivation, and the specific C/EBPβ phosphorylation is mediated by RSK1 downstream of PI3-kinase.

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Molecular Pharmacology: 69 (1)
Molecular Pharmacology
Vol. 69, Issue 1
1 Jan 2006
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Research ArticleArticle

Role of p90 Ribosomal S6-Kinase-1 in Oltipraz-Induced Specific Phosphorylation of CCAAT/Enhancer Binding Protein-β for GSTA2 Gene Transactivation

Seung Jin Lee and Sang Geon Kim
Molecular Pharmacology January 1, 2006, 69 (1) 385-396; DOI: https://doi.org/10.1124/mol.105.018465

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Research ArticleArticle

Role of p90 Ribosomal S6-Kinase-1 in Oltipraz-Induced Specific Phosphorylation of CCAAT/Enhancer Binding Protein-β for GSTA2 Gene Transactivation

Seung Jin Lee and Sang Geon Kim
Molecular Pharmacology January 1, 2006, 69 (1) 385-396; DOI: https://doi.org/10.1124/mol.105.018465
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