3,4-Diaryl-isoxazoles and -imidazoles as Potent Dual Inhibitors of p38α Mitogen Activated Protein Kinase and Casein Kinase 1δ†

2009 ◽  
Vol 52 (23) ◽  
pp. 7618-7630 ◽  
Author(s):  
Christian Peifer ◽  
Mohammed Abadleh ◽  
Joachim Bischof ◽  
Dominik Hauser ◽  
Verena Schattel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Casein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Dual Inhibitors

scholarly journals Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression

1997 ◽  
Vol 323 (3) ◽  
pp. 621-627 ◽  
Author(s):  
Sung-Jin KIM ◽  
Ronald C. KAHN
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Map Kinases ◽  
Nuclear Protein ◽  
Insulin Signalling ◽  
Receptor Activation ◽  
Casein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Intact Cells ◽  
Mitogen Activated Protein

After insulin receptor activation, many cytoplasmic enzymes, including mitogen-activated protein (MAP) kinase, MAP kinase kinase (MEK) and casein kinase II (CKII) are activated, but exactly how insulin signalling progresses to the nucleus remains poorly understood. In Chinese hamster ovary cells overexpressing human insulin receptors [CHO(Hirc)], MEK, CKII and the MAP kinases ERK I and ERK II can be detected by immunoblotting in the nucleus, as well as in the cytoplasm, in the unstimulated state. Nuclear localization of MAP kinase is also observed in 3T3-F442A adipocytes, NIH-3T3 cells and Fao hepatoma cells, whereas MEK is found in the nucleus only in Fao and CHO cells. Insulin treatment for 5–30 min induces a translocation of MEK from the cytoplasm to the nucleus, whereas the MAP kinases and CKII are not translocated into the nucleus in response to insulin during this period. However, nuclear MAP kinase and CKII activities increase by 2–3-fold within 1–10 min after stimulation with insulin. By using gel-shift assays, it has been shown that insulin also stimulates nuclear protein binding to an AP-1 site with kinetics similar to MEK translocation and MAP kinase and CKII activation. Treatment of the extracts in vitro with protein phosphatase 2A or treatment of the intact cells with 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole, a cell-permeable inhibitor of CKII, almost completely blocks the insulin-induced DNA-binding activity, whereas incubation of cells with a MEK inhibitor produces only a slight decrease. These results suggest that insulin signalling results in the activation of serine kinases in the nucleus via two pathways: (1) insulin stimulates the nuclear translocation of some kinases, such as MEK, which might directly phosphorylate nuclear protein substrates or activate other nuclear kinases, and (2) insulin activates nuclear kinases without translocation. The latter is true of CKII, which seems to regulate the binding of nuclear proteins to the AP-1 site, possibly by phosphorylation of AP-1 transcription factors.

Age-Related Changes in Activation of Mitogen-Activated Protein Kinase Cascades by Oxidative Stress

1998 ◽  
Vol 3 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Kathryn Z Guyton ◽  
Myriani Gorospe ◽  
Xiantao Wang ◽  
Yolanda D Mock ◽  
Gertrude C Kokkonen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Age Related ◽  
Mitogen Activated Protein ◽  
Age Related Changes
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