THE TPL-2 PROTOONCOPROTEIN ACTIVATES THE NUCLEAR FACTOR OF ACTIVATED T-CELLS AND INDUCES INTERLEUKIN-2 EXPRESSION IN T-CELL LINES

Tpl-2 expression is induced within 30-60 min after ConA stimulation of rat splenocytes, suggesting that it may contribute to the induction o f IL-2 during T cell activation, Herein we show that wild-type and car boxyl-terminally truncated (activated) Tpl-2 activate the nuclear fact or of activated T cells (NEAT) and induce interleukin 2 (IL-2) express ion in EL4 cells, In Jurkat cells the truncated Tpl-2 activates NEAT a nd induces IL-2, whereas wild-type Tpl-2 activates NFAT only when cotr ansfected with NEAT expression constructs, suggesting that Tpl-2 may i nduce NFAT activation signals, Experiments in NIH 3T3 cells revealed t hat the NFATp isoform, but not the NFATc or NFATx isoform, undergoes n uclear translocation when coexpressed with wildtype Tpl-2 and confirme d this hypothesis, Activation of NEAT by anti-CD3 stimulation but not by phorbol 12-myristate 13-acetate and ionomycin in Jurkat cells was i nhibited by the kinase-dead Tpl-2K167M, suggesting that Tpl-2 contribu tes to the transduction of NEAT activation signals originating in the T cell receptor, The Tpl-2-mediated induction of IL-2 was not observed in T cell lymphoma lines other than EL3 and Jurkat, as well as in nor mal T cells, NFAT activation by Tpl-2, however, was observed in severa l cell lines including some of nonhematopoietic origin, The activation of NFAT by Tpl-2 in different cell types defines a molecular mechanis m that may contribute to its oncogenic potential.