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This project work builds on previous exciting collaborative research between the Alessi lab and AstraZeneca that indicated that SGK protein kinases play critical roles in driving proliferation and survival of cancer cells (Sommer EM et al., Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors, Biochem J.
The GC-GR complex then migrates to the nucleus, binds to the glucocorticoid response element, and activates the transcription of target genes, including MKP-1 , GILZ , and SGK1 . Via binding to the receptor, GCs are able to inhibit p38 MAPK by inducing MKP-1, which in turn results in de-phosphorylation of p38. MKP-1 is a phosphatase that dephosphorylates and inactivates MAPKs, including p38 MAPK, and inhibits production of pro-inflammatory cytokines, which is critical for the anti-inflammatory functions of GCs. Clark et al . proposed that MKP-1 played a role in the inhibition of p38 MAPK and the consequent destabilization of pro-inflammatory mRNAs by GCs.
Regions of GR binding in the mouse serum/glucocorticoid regulated kinase 1 (Sgk1) and period circadian clock 1 (Per1) genes have been previously described (Yu et al.
Sawabe et al., "Abnormal expression of ENaC and SGK1 mRNA induced by dietary sodium in Dahl saltsensitively hypertensive rats," Cell Biology International, vol.
Genes regulated by Number of Network node transcription factors transcription (Figure 2) factors regulating the target genes IL-6 4 30 MAPK14 3 -- RELA 3 11 FOS 3 13 JUN 2 13 NF-kappa 1 2 14 IL-1b 2 16 COL11 2 -- EGR1 2 18 EGR3 2 -- FOSb 2 -- IL-13 2 -- IL-5 2 10 SGK1 2 -- SMAD2 2 10 SRC 2 -- Table 4: Network node statistics.
Additional studies are needed to further elucidate the potential role of mTOR/ SGK1 and INS docking proteins INS receptor substrates 1 and 2 as mediators of the efficacy of SIT on insulin resistance.
Zhou et al., "Response of human nonsmall-cell lung cancer cells to the influence of Wogonin with SGK1 dynamics," Acta Biochimica et Biophysica Sinica, vol.
Zhao et al., "Icariin alters the expression of glucocorticoid receptor, FKBP5 and SGK1 in rat brains following exposure to chronic mild stress," International Journal of Molecular Medicine, vol.
Fujita, "Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1," Hypertension, vol.
Wang, "Insulin up-regulates epithelial sodium channel in LPS-induced acute lung injury model in rats by SGK1 activation," Injury, vol.
Thus, it has been reported that high concentrations of sodium induce the activation of the p38 protein kinase and the nuclear factor NFAT5 as well as the synthesis and activation of the serum and glucocorticoid-regulated kinase 1 or SGK1; this kinase in turn induces the expression of the receptor for IL-23 and thus favors the differentiation of Th17 cells and the release of proinflammatory cytokines .
It is mainly activated by growth factors and it preferentially phosphorylates and activates proteins belonging to the AGC protein kinases family including AKT (Ser 473) and SGK1 (Ser 422).
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