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

National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea

Oltipraz, which has been extensively studied as a cancer chemopreventive agent, promotes phosphatidylinositol 3-kinase-mediated activation of CCAAT/enhancer binding protein- (C/EBP). Activated p90 ribosomal S6-kinase-1 (RSK1) phosphorylates major transcription factors, including C/EBP. This study examined whether oltipraz induces phosphorylation of C/EBP at specific residues, and if so, whether RSK1 regulates C/EBP phosphorylation by oltipraz for the GSTA2 gene transactivation. Subcellular fractionation and immunoblot analyses revealed that oltipraz treatment increased the level of C/EBP 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/EBP 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/EBP 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/EBP 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/EBP. 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/EBP at Ser¹⁰⁵ (functionally analogous Thr^217/266 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/EBP phosphorylation is mediated by RSK1 downstream of PI3-kinase.

Address correspondence to: Dr. Sang Geon Kim, College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, South Korea. E-mail: sgk{at}snu.ac.kr

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