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p38 MAPK mediates TNF-induced apoptosis in endothelial cells via phosphorylation and downregulation of Bcl-x(L).
| Content Provider | Semantic Scholar |
|---|---|
| Author | Grethe, Simone Andersson, Tommy |
| Copyright Year | 2004 |
| Abstract | The role of p38 mitogen-activated protein kinase (MAPK) in apoptosis is a matter of debate. Here, we investigated the involvement of p38 MAPK in endothelial apoptosis induced by tumor necrosis factor alpha (TNF). We found that activation of p38 MAPK preceded activation of caspase-3, and the early phase of p38 MAPK stimulation did not depend on caspase activity, as shown by pretreatment with the caspase inhibitors z-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and Boc-Asp(OMe)-fluoromethylketone (BAF). The p38 MAPK inhibitor SB203580 significantly attenuated TNF-induced apoptosis in endothelial cells, suggesting that p38 MAPK is essential for apoptotic signaling. Furthermore, we observed a time-dependent increase in active p38 MAPK in the mitochondrial subfraction of cells exposed to TNF. Notably, the level of Bcl-x(L) protein was reduced in cells undergoing TNF-induced apoptosis, and this reduction was prevented by treatment with SB203580. Immunoprecipitation experiments revealed p38 MAPK-dependent serine-threonine phosphorylation of Bcl-x(L) in TNF-treated cells. Exposure to lactacystin prevented both the downregulation of Bcl-x(L) and activation of caspase-3. Taken together, our results suggest that TNF-induced p38 MAPK-mediated phosphorylation of Bcl-x(L) in endothelial cells leads to degradation of Bcl-x(L) in proteasomes and subsequent induction of apoptosis. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://lup.lub.lu.se/search/ws/files/4468772/545215.pdf |
| PubMed reference number | 15265709v1 |
| Volume Number | 298 |
| Issue Number | 2 |
| Journal | Experimental cell research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Alanine BCL-XL Protein Caspase Inhibitors Down-Regulation Endothelial Cells Endothelium Mitogen-Activated Protein Kinases Mitogens N-tert-butyloxycarbonylnorleucyl-leucyl-phenylalanine Positive Regulation of Apoptosis SB 203580 Threonine Tumor Necrosis Factor-alpha Valine apoptotic signaling pathway benzyloxycarbonyl-Phe-Ala-fluormethylketone caspase activity caspase-3 lactacystin multicatalytic endopeptidase complex |
| Content Type | Text |
| Resource Type | Article |
