IL-6 activates serum and glucocorticoid kinase via p38α mitogen-activated protein kinase pathway
| Autor: | Silvia Taffetani, Yoko Yamagiwa, Tushar Patel, Jiahuai Han, Fanyin Meng |
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| Rok vydání: | 2005 |
| Předmět: |
Pyridines
Physiology medicine.medical_treatment Protein Serine-Threonine Kinases Article Immediate early protein Immediate-Early Proteins Mitogen-Activated Protein Kinase 14 Enzyme activator Cell Line Tumor medicine Humans RNA Messenger Enzyme Inhibitors Autocrine signalling biology Interleukin-6 Kinase Imidazoles Nuclear Proteins Cell Biology Cell biology Enzyme Activation Isoenzymes Cytokine Gene Expression Regulation Mitogen-activated protein kinase Cancer research biology.protein Signal transduction Glucocorticoid Signal Transduction medicine.drug |
| Zdroj: | American Journal of Physiology-Cell Physiology. 289:C971-C981 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00081.2005 |
| Popis: | 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. 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 Ser78. Pretreatment with the pharmacological inhibitors of p38 MAPK SB-203580 or SB-202190 blocked IL-6-induced SGK phosphorylation at Ser78and SGK activation. Overexpression of p38α increased constitutive SGK phosphorylation at Ser78, whereas dominant negative p38α MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38α 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. |
| Databáze: | OpenAIRE |
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