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J. Biol. Chem., Vol. 278, Issue 9, 6992-7000, February 28, 2003

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Treatment of Human T Cells with Bisperoxovanadium Phosphotyrosyl Phosphatase Inhibitors Leads to Activation of Cyclooxygenase-2 Gene^*

Corinne Barat and Michel J. Tremblay

From the Centre de Recherche en Infectiologie, Hôpital CHUL, Centre Hospitalier, Universitaire de Québec and Département de Biologie Médicale, Faculté de Médecine, Université Laval, Ste-Foy, Québec G1V 4G2, Canada

Protein-tyrosine phosphatase (PTP) inhibitors are potent activators of T lymphocytes, most likely by affecting the early steps of T cell receptor (TCR) signaling. We have analyzed the effect of the PTP inhibitor bisperoxovanadium (bpV) on expression of the human cyclooxygenase 2 (COX-2) gene, which is induced following TCR triggering. Here we show that COX-2 promoter activity is markedly up-regulated following exposure of Jurkat T cells to bpV(pic). Interestingly enough, treatment of Jurkat cells with cyclic AMP-elevating agents such as forskolin, in combination with bpV, resulted in a more important COX-2 transcriptional activation. Such activation is inhibited by the immunosuppressive drugs FK506 and cyclosporin A. The two nuclear factor of activated T cells (NFAT) binding sites located within the COX-2 promoter region are involved in bpV-mediated positive effect on COX-2 promoter. Electromobility shift assays showed that NFAT1 and activator protein-1 are both translocated to the nucleus following bpV treatment. The active participation of p56^lck, ZAP-70, p36^LAT, and calcium in the bpV-dependent signaling cascade leading to COX-2 transcriptional activation was demonstrated using deficient cell lines and specific inhibitors. Although several PTPs are most likely targeted by bpV, our data suggest that the bpV-mediated signaling cascade is initiated by inhibition of SHP-1, which leads to phosphorylation of p56^lck and ZAP-70 and, ultimately, to NFAT and activator protein-1 nuclear translocation. These results suggest that PTP inhibitors can activate COX-2 gene expression in a manner very similar to the stimulation induced by TCR triggering.

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