%0 Journal Article
%T Signal transduction mechanisms involved in S100A4-induced activation of the transcription factor NF-百B
%A Ida Grotterˋd
%A Gunhild M Mˋlandsmo
%A Kjetil Boye
%J BMC Cancer
%D 2010
%I BioMed Central
%R 10.1186/1471-2407-10-241
%X The human osteosarcoma cell line II-11b was stimulated with recombinant S100A4 in the presence or absence of inhibitors of common signal transduction pathways, and NF-百B activity was examined using a luciferase-based reporter assay and phosphorylation of I百B汐. mRNA expression was analyzed by real-time RT-PCR, protein expression was examined by Western blotting and IKK activity was measured using an in vitro kinase assay. The role of upstream kinases and the cell surface receptor RAGE was investigated by overexpression of dominant negative proteins and by siRNA transfection.The Ser/Thr kinase inhibitors H-7 and staurosporine inhibited S100A4-induced I百B汐 phosphorylation and subsequent NF-百B activation. The protein tyrosine kinase inhibitor genistein and the phospholipase C inhibitor compound 48/80 had a partial inhibitory effect on I百B汐 phosphorylation, whereas inhibitors of protein kinase C, G-protein coupled receptors and PI 3-kinases had no effect on the level of phosphorylation. Interestingly, S100A4 treatment induced activating phosphorylations of IKK汐/汕, but neither H-7 nor staurosporine was able to significantly inhibit IKK activation. Dominant negative MEKK1 or NIK did not inhibit S100A4-induced NF-百B activity, and S100A4 stimulation did not influence AKT phosphorylation. Furthermore, diminished expression of the putative S100 protein receptor RAGE did not affect the observed phosphorylation of I百B汐.S100A4 activates NF-百B by inducing phosphorylation of IKK汐/汕, leading to increased I百B汐 phosphorylation. The Ser/Thr kinase inhibitors H-7 and staurosporine attenuated S100A4-induced NF-百B activation and inhibited IKK-mediated phosphorylation of I百B汐. S100A4-induced NF-百B activation was independent of the putative S100 protein receptor RAGE and the Ser/Thr kinases MEKK1, NIK and AKT. These findings lead to increased understanding of S100A4 signaling, which may contribute to the identification of novel targets for anti-metastatic therapy.The metastasis-promoting pr
%U http://www.biomedcentral.com/1471-2407/10/241