Complete Inhibition of Anisomycin and UV Radiation but Not Cytokine Induced JNK and p38 Activation by an Aryl-substituted Dihydropyrrolopyrazole Quinoline and Mixed Lineage Kinase 7 Small Interfering RNA
| Autor: | Mary M. Mader, Michael E. Christe, Xushan Wang, Laura J. Bloem, Jeffrey K. Smallwood, Najia Jin, Theodore Goodson, Arindam Chatterjee, Xiaohong Yu, William F. Matter, John E. Toth, Robert M. Campbell, Chris J. Vlahos |
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| Rok vydání: | 2005 |
| Předmět: |
Time Factors
MAP Kinase Kinase 4 Muscle Proteins Apoptosis Mitogen-activated protein kinase kinase p38 Mitogen-Activated Protein Kinases Biochemistry MAP2K7 Mice chemistry.chemical_compound Transgenes Enzyme Inhibitors RNA Small Interfering Anisomycin Glutathione Transferase Kinase MAP Kinase Kinase Kinases COS Cells Quinolines Cytokines Electrophoresis Polyacrylamide Gel Plasmids Signal Transduction Ultraviolet Rays p38 mitogen-activated protein kinases Blotting Western DNA Fragmentation Protein Serine-Threonine Kinases Biology Transfection Catalysis Inhibitory Concentration 50 Animals Humans Protein kinase A Molecular Biology Nucleic Acid Synthesis Inhibitors Mitogen-Activated Protein Kinase Kinases Dose-Response Relationship Drug MAP kinase kinase kinase Tumor Necrosis Factor-alpha Myocardium JNK Mitogen-Activated Protein Kinases Cell Biology Molecular biology Enzyme Activation Models Chemical chemistry Pyrazoles Cyclin-dependent kinase 9 Interleukin-1 |
| Zdroj: | Journal of Biological Chemistry. 280:19298-19305 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m413059200 |
| Popis: | Mixed lineage kinase 7 (MLK7) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the pro-apoptotic signaling pathways p38 and JNK. A library of potential kinase inhibitors was screened, and a series of dihydropyrrolopyrazole quinolines was identified as highly potent inhibitors of MLK7 in vitro catalytic activity. Of this series, an aryl-substituted dihydropyrrolopyrazole quinoline (DHP-2) demonstrated an IC50 of 70 nM for inhibition of pJNK formation in COS-7 cell MLK7/JNK co-transfection assays. In stimulated cells, DHP-2 at 200 nM or MLK7 small interfering RNA completely blocked anisomycin and UV induced but had no effect on interleukin-1beta or tumor necrosis factor-alpha-induced p38 and JNK activation. Additionally, the compound blocked anisomycin and UV-induced apoptosis in COS-7 cells. Heart tissue homogenates from MLK7 transgenic mice treated with DHP-2 at 30 mg/kg had reduced JNK and p38 activation with no apparent effect on ERK activation, demonstrating that this compound can be used to block MLK7-driven MAPK pathway activation in vivo. Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stress-activated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo. |
| Databáze: | OpenAIRE |
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