ROLE OF THE FAS FAS LIGAND PATHWAY IN APOPTOTIC CELL-DEATH INDUCED BYTHE HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE-I TAX TRANSACTIVATOR/

Two distinct human diseases have been described in association with hu man T cell lymphotropic virus type I (HTLV-I) infection: adult T cell leukaemia and tropical spastic paraparesis/HTLV-I-associated myelopath y, Although comprehensive understanding of specific mechanisms underly ing pathogenesis of either disease has not yet been achieved, the vira l regulatory protein Tax is believed to play a significant role, Previ ous studies demonstrated the potential of Tax to transform host cells, Here, it is shown that the Tax transactivator has in addition the pot ential to induce T cell death by apoptosis. Using an inducible system (Jurkat cell line JPX-9), significant apoptotic cell death upon Tax ex pression was observed, In an attempt to detect the cellular genes medi ating this effect, it was found that induction of Tax was associated w ith marked upregulation of the Fas ligand (Fast) gene, Tax-induced apo ptosis was inhibited when the Fas/FasL pathway was interrupted by YVAD -cmk, the inhibitor of ICE-like proteases, Transient expression experi ments provided additional support for the putative role of endogenous Fast in Tax-induced apoptosis, Upon cotransfection with Tax-expressing plasmid, the transcriptional activity of the Fast promoter was found to be significantly upregulated in Jurkat cells and several other cell lines, as measured by reporter gene expression, Furthermore, cotransf ection using different Tax mutants demonstrated that both CREB and NF- KB activation domains of Tax protein were required for the transactiva tion to take effect.