INDUCTION OF INTERLEUKIN-2 TRANSCRIPTION BY THE HAMSTER POLYOMAVIRUS MIDDLE T-ANTIGEN - A ROLE FOR FYN IN T-CELL SIGNAL-TRANSDUCTION

The transforming protein of mouse polyomavirus, the mouse middle T ant igen (MomT), and its counterpart in the hamster polyomavirus, the hams ter middle T antigen (HamT), interact with a number of cellular protei ns. Among these are members of the Src family of tyrosine kinases, the phosphatidylinositol 3-kinase, the serine/threonine phosphatase PP2A and the adaptor protein She (in the case of MomT). However, both the r elative affinity of these antigens for the members of the Src family a nd the tumor profile induced by their respective viruses are quite dis tinct. Particularly noteworthy are the preferential binding of Fyn by HamT and the induction of lymphoid malignancies by the hamster polyoma virus. Here we report that, when expressed in fibroblasts, HamT also a ssociated with phospholipase C gamma (PLC gamma), which led to an incr eased intracellular concentration of inositol-1, 4, 5-trisphosphate. W e also show that expression of HamT in the mouse T cell line ELA was s ufficient to induce transcription from interleukin-2 (IL-2), NFAT and NF kappa B reporter constructs. The immunosuppressant FK506 as well as dominant negative alleles of Ras and Raf inhibited HamT-induced IL-2 transcription. This, together with the observation of NFAT responses, suggests that the action of HamT depended at least in part on the inte grity of signal transduction pathways elicited by activated PLC gamma. Furthermore, dominant negative Fyn but not the equivalent allele of L ck blocked HamT activation of IL-2 transcription, while both Lck and F yn dominant negative aIleIes blocked LT cell receptor-mediated IL-2 tr anscriptional activation. These results support the hypothesis that Fy n is involved in signal transduction events leading to IL-2 transcript ional activation in T cells. Finally, the activation of IL-2 transcrip tion by HamT and not by MomT shown here parallels the ability of the h amster polyomavirus to induce lymphoid malignancies.