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Received for publication August 30, 2005.
Revised October 21, 2005.
Accepted for publication October 24, 2005.
for GSTA2 Gene Transactivation
Oltipraz, which has been extensively studied as a cancer chemopreventive agent, promotes phosphatidylinositol 3-kinase (PI3-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 CBP 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 phosphorylation of rat C/EBP at Ser105 (functionally analogous Thr217/266 in mouse and human forms) in hepatocytes, which results in CBP recruitment for the GSTA2 gene transactivation, and the specific C/EBP phosphorylation is mediated by RSK1 downstream of PI3-kinase.
Key words:
Glutathione S-transferases, Regulation - transcriptional
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