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  • Title: Tyrosine phosphatase-dependent/tyrosine kinase-independent induction of nuclear factor-kappa B by tumor necrosis factor-alpha: effects on prostaglandin endoperoxide synthase-2 mRNA accumulation.
    Author: Mahboubi K, Young W, Ferreri NR.
    Journal: J Pharmacol Exp Ther; 1998 May; 285(2):862-8. PubMed ID: 9580637.
    Abstract:
    We previously have demonstrated that tumor necrosis factor-alpha (TNF-alpha) increases prostaglandin endoperoxide synthase-2 (PGHS-2) mRNA accumulation and tyrosine phosphorylation in the fibrosarcoma cell line, MCA-101. Tyrosine kinase inhibitor, genistein, and tyrosine phosphatase inhibitor, phenylarsine oxide (PAO), blocked TNF-alpha-mediated induction of PGHS-2 mRNA in these cells. Because the PGHS-2 promoter has a nuclear factor-kappa B (NF-kappa B) binding motif, which is important for PGHS-2 gene transcription in some cell types, we have evaluated the effects of tyrosine kinase inhibitors and PAO on TNF-alpha-induced NF-kappa B activation. TNF-alpha (1 nM) rapidly induced translocation of NF-kappa B, an event accompanied by degradation of inhibitory protein I kappa B-alpha. N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a serine protease inhibitor, inhibited I kappa B-alpha degradation and NF-kappa B activation in response to TNF-alpha in a dose-dependent manner (25, 50, 100 microM). TPCK also inhibited PGHS-2 mRNA accumulation. These data suggest that NF-kappa B contributed to PGHS-2 mRNA accumulation in MCA-101 cells stimulated with TNF-alpha. PAO (2.4 microM) completely abolished activation of NF-kappa B and degradation of I kappa B-alpha induced by TNF-alpha at a concentration that blocked PGHS-2 mRNA accumulation. However, four tyrosine kinase inhibitors, genistein, tyrphostin 47, herbimycin A and erbstatin, failed to block translocation of NF-kappa B and degradation of I kappa B-alpha. These data demonstrate that tyrosine kinase pathways are not required for TNF-alpha-induced NF-kappa B activation in MCA-101 cells and suggest that signaling via these pathways mediates TNF-alpha-induced PGHS-2 mRNA accumulation via an NF-kappa B-independent mechanism. Moreover, an upstream tyrosine phosphatase pathway may mediate PGHS-2 mRNA accumulation by TNF-alpha via an NF-kappa B-dependent mechanism.
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