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Mitogen Activated Protein Kinase pathway
1 Scott & White Clinic, Texas A&M University System HSC College of Medicine, Temple, Texas, USA
* To whom correspondence should be addressed. E-mail: tpatel{at}swmail.sw.org.
Interleukin-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. The serum and glucocorticoid stimulated kinase (SGK) has been implicated as a survival kinase but its role in survival signaling by IL-6 is unknown. Following IL-6 stimulation, p38 MAPK activation preceded phosphorylation of SGK at Ser78. Pre-treatment with the pharmacological inhibitors of p38 MAPK SB203580 or SB202190 blocked IL-6 induced SGK phosphorylation at Ser78 and SGK activation. Overexpression of p38
increased constitutive SGK phosphorylation at Ser78, whereas dominant negative p38 MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38 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.
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