Inhibition of the expression of mitogen-activated protein phosphatase-1 potentiates apoptosis induced by tumor necrosis factor-alpha in rat mesangial cells.
Previously we showed that rat mesangial cells are normally resistant to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. They are made susceptible to the apoptotic effect of TNF-alpha when pretreated with actinomycin D, cycloheximide or vanadate. A sustained c-Jun N-terminal protein kinase (JNK) activation was closely correlated with the initiation of apoptosis under these conditions. We proposed that a TNF-alpha-inducible phosphatase was responsible for preventing a sustained activation of JNK and consequent apoptosis in these cells (Guo, Y.-L., Baysal, K., Kang, B. , Yang, L.-J., and Williamson, J. R. (1998) J. Biol. Chem. 273, 4027-4034). In the present study we provide further evidence to support this hypothesis. Ro318220, although originally identified as a specific inhibitor of protein kinase C, was subsequently found to be a strong inhibitor of MKP-1 expression. In rat mesangial cells, pretreatment of the cells with Ro318220 blocked expression of MKP-1 induced by TNF-alpha. This treatment also prolonged JNK activation and caused apoptosis. Taken together, our results support the currently controversial hypothesis that the JNK pathway is involved in TNF-alpha-induced apoptosis. In addition, we provide a mechanistic explanation for how mesangial cells in primary culture achieve resistance to TNF-alpha cytotoxicity. Specifically, induction of MKP-1 by TNF-alpha appears to be responsible for protection of the cells from apoptosis by preventing a prolonged activation of JNK.
Guo
Y L
YL
Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kang
B
B
Williamson
J R
JR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D007211:Indoles; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; C064758:Ro 31-8220