The involvement of protein tyrosine kinase activity in a tumor necrosis factor resistance mechanism.
Certain cytokines activate pathways involving protein phosphorylation. Serine and threonine phosphorylation are most common, whereas tyrosine phosphorylation is a rare post-translational event, accounting for a very small percentage of phosphorylated amino acids. Nonetheless, protein tyrosine kinase activity is associated with several cell surface receptors and is involved in intracellular signaling. Here, we show that tumor necrosis factor (TNF) treatment of cells resistant to TNF-mediated lysis resulted in an increase in protein tyrosine kinase activity. Moreover certain TNF-resistant cell lines became sensitive to TNF-mediated cytolysis when treated with the inhibitors of protein tyrosine kinases, genistein, and herbimycin A. In contrast, genistein had no effect on the lysis a TNF-sensitive cell line. The increase in TNF-mediated lysis affected by genistein occurred only when it was present during TNF treatment, and the effect was maximal when the inhibitor was added 30 min after the TNF. These findings suggest that, in TNF-resistant cells, TNF activates a protein tyrosine kinase that contributes to the cell's resistance to lysis and this resistance mechanism does not function in the TNF-sensitive cell line.
Sasaki
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Department of Microbiology, University of Hawaii, Honolulu 96822, USA.
Patek
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D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004351:Drug Resistance; D005347:Fibroblasts / Q000378:metabolism; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D051379:Mice; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014638:Vanadates / Q000494:pharmacology
D016227:Benzoquinones; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D011809:Quinones; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D017828:Rifabutin; D014638:Vanadates; C020754:herbimycin; D003513:Cycloheximide; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases