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dc.contributor.authorMeng, F. M.zh_CN
dc.contributor.authorYamagiwa, Y.zh_CN
dc.contributor.authorTaffetani, S.zh_CN
dc.contributor.authorHan, J. H.zh_CN
dc.contributor.authorPatel, T.zh_CN
dc.identifier.citationAmerican Journal of Physiology-Cell Physiology,289(4):C971-C981zh_CN
dc.description.abstractInterleukin-6 (IL-6) has been implicated as an autocrine factor involved in growth of several human cancers, such as tumors arising from the biliary tract or cholangiocarcinoma. In malignant biliary tract epithelia, IL-6 activates the p38 MAPK pathway, which mediates a dominant survival signaling pathway. Serum and glucocorticoid-stimulated kinase (SGK) has been implicated as a survival kinase, but its role in survival signaling by IL-6 is unknown. After IL-6 stimulation, p38 MAPK activation preceded phosphorylation of SGK at Ser(78). Pretreatment with the pharmacological inhibitors of p38 MAPK SB-203580 or SB-202190 blocked IL-6-induced SGK phosphorylation at Ser78 and SGK activation. Overexpression of p38 alpha increased constitutive SGK phosphorylation at Ser78, whereas dominant negative p38 alpha MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38 alpha MAPK overexpression increased SGK mRNA and protein expression. An increase in p38 MAPK and SGK occurred following enforced expression of IL-6 in vivo. Furthermore, inhibition of SGK expression by siRNA increased toxicity due to chemotherapeutic drugs. Taken together, these data identify SGK as both a downstream kinase substrate as well as a transcriptionally regulated gene target of p38 MAPK in response to IL-6 and support a role of SGK during survival signaling by IL-6 in human cancers, such as cholangiocarcinoma.zh_CN
dc.subjectintracellular kinaseszh_CN
dc.titleIL-6 activates serum and glucocorticoid kinase via p38 alpha mitogen-activated protein kinase pathwayzh_CN

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