p38 MAPK regulates phosphorylation of Bad via PP2A-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-α induced endothelial apoptosis
Autor: | Simone Grethe, M. Isabella Pörn-Ares |
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Rok vydání: | 2006 |
Předmět: |
MAPK/ERK pathway
Programmed cell death Cell Survival Pyridines p38 mitogen-activated protein kinases MAP Kinase Kinase 2 MAP Kinase Kinase 1 Down-Regulation Apoptosis Polyenes macromolecular substances Alkenes p38 Mitogen-Activated Protein Kinases environment and public health Cell Line chemistry.chemical_compound Downregulation and upregulation Phosphoprotein Phosphatases Humans Protein Phosphatase 2 Phosphorylation Fostriecin Oxazoles Cells Cultured Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Tumor Necrosis Factor-alpha Chemistry Imidazoles Endothelial Cells Cell Biology Protein phosphatase 2 Cell biology enzymes and coenzymes (carbohydrates) Pyrones Marine Toxins bcl-Associated Death Protein Signal Transduction Calyculin |
Zdroj: | Cellular Signalling. 18:531-540 |
ISSN: | 0898-6568 |
DOI: | 10.1016/j.cellsig.2005.05.023 |
Popis: | We recently reported that p38 MAPK regulates TNF-induced endothelial apoptosis via phosphorylation and downregulation of Bcl-xL. Here, we describe that such apoptosis includes p38 MAPK-mediated, protein phosphatase 2A (PP2A)-dependent, downregulation of the MEK-ERK pathway. Inhibition of PP2A with fostriecin or calyculin A significantly increased MEK phosphorylation, as did exposure to the p38 MAPK inhibitor SB203580. Inhibition of MEK potentiated TNF-induced caspase-3 activity and cell death, and both those events were suppressed by treatment with fostriecin or calyculin A. Immunoprecipitation experiments revealed an association between p38 MAPK, PP2A and MEK, and the results of a phosphatase assay suggested that PP2A is a downstream target of p38 MAPK. Importantly, phosphorylation of Bad at Ser-112 was found to be regulated by p38 MAPK and PP2A. In summary, the present findings indicate a novel p38 MAPK-mediated apoptosis pathway, involving activation of Bad via PP2A-dependent inhibition of the MEK-ERK pathway. |
Databáze: | OpenAIRE |
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