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      Casein kinase II-mediated phosphorylation of NF-kappaB p65 subunit enhances inducible nitric-oxide synthase gene transcription in vivo.

      The Journal of Biological Chemistry

      Animals, Blotting, Northern, Casein Kinase II, Cell Line, Cell Line, Tumor, Cell Nucleus, metabolism, Cytoplasm, DNA, Enzyme Activation, Genes, Reporter, Immunoblotting, Interleukin-1, Kinetics, Lipopolysaccharides, Mice, Microscopy, Fluorescence, Mutagenesis, Site-Directed, NF-kappa B, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Phosphorylation, Plasmids, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Serine, chemistry, Time Factors, Transcription Factor RelA, Transcription, Genetic, Transcriptional Activation, Transfection

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          Nitric oxide (NO) produced by inducible nitric-oxide synthase (NOSII) is mainly regulated at the transcriptional level by the nuclear factor-kappaB (NF-kappaB). In the present study, we further analyzed the role of NF-kappaB in the in vivo transcriptional regulation of NOSII gene by comparing two clones isolated from the EMT-6 mouse mammary cancer cell line. In response to interleukin (IL)-1beta or lipopolysaccharide (LPS), EMT-6 clone J (EMT-6J) cells produce 3-fold more NO than EMT-6 clone H (EMT-6H) cells, an effect correlated with enhanced activation of NF-kappaB in EMT-6J cells. In response to IL-1beta, the kinetics of degradation of NF-kappaB inhibitors IkappaB-alpha and IkappaB-beta, the nucleo-cytoplasmic shuttling of the transcription factor and its binding to a specific DNA sequence were similar in both clones. In contrast, an IL-1beta-induced phosphorylation of serine residues in NF-kappaB p65 subunit was observed in EMT-6J, but not in EMT-6H, cells. This IL-1beta-induced phosphorylation of p65 was specifically prevented by pretreatment of EMT-6J cells with the casein kinase II inhibitor DRB. Small interfering RNA-mediated depletion of casein kinase II-alpha subunit also decreased NF-kappaB transcriptional activity and NOSII gene transcription in IL-1beta and LPS-stimulated EMT-6J cells to the levels observed in EMT-6H cells treated in the same conditions. Altogether, these data indicate that casein kinase II-mediated phosphorylation of p65 subunit can enhance the transcriptional activity of NF-kappaB in vivo. This post-translational modification of the transcription factor can be responsible for increased NOSII gene transcription and NO production in tumor cells exposed to either IL-1beta or LPS.

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