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The serine\u2010threonine phosphatase inhibitors, okadaic acid (OKA) and calyculin A (CLA), synergistically augmented TNF\u2010induced apoptosis in several TNF\u2010sensitive tumor cell lines including the U937 histiocytic lymphoma, the BT\u201020 mammary carcinoma, and the LNCap prostatic tumor cell line. Furthermore, the phosphatase inhibitors completely reversed the TNF resistance of a variant (U9\u2010TR) derived from U937. CLA also inhibited phosphatase activity in cell\u2010free extracts from both U937 and U9\u2010TR at the same concentrations (0.4\u20132.0 nM) that it synergized with TNF. In contrast, TNF treatment of U937 cells did not result in inhibition of phosphatase activity mediated by protein phosphatase 1 (PP1) and PP2A in cell extracts. Since the phosphatase inhibitors are known to increase the overall levels of protein phosphorylation in cells, this suggested that TNF may act by stimulating protein kinase (PK) activity. This hypothesis was supported by the results of testing a panel of relatively specific protein kinase inhibitors. TNF activation of DNA fragmentation was blocked by a potent inhibitor of myosin light chain kinase (MLCK) but was unaffected by inhibitors of cAMP or cGMP\u2010dependent PKs. We postulate that a defect in the activation of MLCK or possibly some other as yet unknown PK may be responsible for the TNF resistance of U9\u2010TR. Furthermore, this resistance may be circumvented by promoting protein phosphorylation with the serine\u2010threonine\u2010dependent phosphatase inhibitors.<\/jats:p>","DOI":"10.1002\/jcb.240530307","type":"journal-article","created":{"date-parts":[[2005,5,28]],"date-time":"2005-05-28T21:07:01Z","timestamp":1117314421000},"page":"222-233","source":"Crossref","is-referenced-by-count":25,"title":["Role of protein phosphorylation in TNF\u2010induced apoptosis: Phosphatase inhibitors synergize with TNF to activate DNA fragmentation in normal as well as TNF\u2010resistant U937 variants"],"prefix":"10.1002","volume":"53","author":[{"given":"Susan 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