Two distinct human diseases have been described in association with human T cell lymphotropic virus type I (HTLV-I) infection: adult T cell leukaemia and tropical spastic paraparesis/HTLV-I-associated myelopathy. Although comprehensive understanding of specific mechanisms underlying pathogenesis of either disease has not yet been achieved, the viral regulatory protein Tax is believed to play a significant role. Previous studies demonstrated the potential of Tax to transform host cells. Here, it is shown that the Tax transactivator has in addition the potential to induce T cell death by apoptosis. Using an inducible system (Jurkat cell line JPX-9), significant apoptotic cell death upon Tax expression was observed. In an attempt to detect the cellular genes mediating this effect, it was found that induction of Tax was associated with marked up- regulation of the Fas ligand (FasL) gene. Tax- induced apoptosis was inhibited when the Fas/FasL pathway was interrupted by YVAD-cmk,the inhibitor of ICE-like proteases. Transient expression experiments provided additional support for the putative role of endogenous FasL in Tax-induced apoptosis. Upon cotransfection with Tax-expressing plasmid, the transcriptional activity of the FasL promoter was found to be significantly upregulated in Jurkat cells and several other cell lines, as measured by reporter gene expression. Furthermore, cotransfection using different Tax mutants demonstrated that both CREB and NF-k -B activation domains of Tax protein were required for the transactivation to take effect.
AldersonM. R., ToughT. W., David-SmithT., BraddyS., FalkB., SchooleyK. A., GoodwinR. G., SmithC. A., RamsdellF., LynchD. H.1995; Fas ligand mediates activation-induced cell death in human T lymphocytes. Journal of Experimental Medicine 181:781–786
ArimaN., MolitorJ. A., SmithM. R., KimJ. H., DaitokuY., GreeneW. C.1991; Human T-cell leukemia virus type I Tax induces expression of the Rel-related family of kappa B enhancer-binding proteins: evidence for a pretranslational component of regulation. Journal of Virology 65:6892–6899
CannA. J., RosenblattJ. D., WachsmanW., ShahN. P., ChenI. S.1985; Identification of the gene responsible for human T-cell leukaemia virus transcriptional regulation. Nature 318:571–574
DebatinK. M., GoldmannC. K., BamfordR., WaldmannT. A., KrammerP. H.1990; Monoclonal-antibody-mediated apoptosis in adult T-cell leukaemia. Lancet 335:497–500
FujiiM., TsuchiyaH., ChuhjoT., AkizawaT., SeikiM.1992; Interaction of HTLV-1 Tax1 with p67SRF causes the aberrant induction of cellular immediate early genes through CArG boxes. Genes & Development 6:2066–2076
FurukawaY., OsameM., KubotaR., TaraM., YoshidaM.1995; Human T-cell leukemia virus type-1 (HTLV-1) Tax is expressed at the same level in infected cells of HTLV-1-associated myelopathy or tropical spastic paraparesis patients as in asymptomatic carriers but at a lower level in adult T-cell leukemia cells. Blood 85:1865–1870
GessainA., BarinF., VernantJ. C., GoutO., MaursL., CalenderA., de TheG.1985; Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 2:407–410
GrossmanW. J., KimataJ. T., WongF. H., ZutterM., LeyT. J., RatnerL.1995; Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I. Proceedings of the National Academy of Sciences, USA 92:1057–1061
ImadaK., Takaori-KondoA., AkagiT., ShimotohnoK., SugamuraK., HattoriT., YamabeH., OkumaM., UchiyamaT.1995; Tumorigenicity of human T-cell leukemia virus type I-infected cell lines in severe combined immunodeficient mice and characterization of the cells proliferating in vivo. Blood 86:2350–2357
InoueJ., SeikiM., TaniguchiT., TsuruS., YoshidaM.1986; Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO Journal 5:2883–2888
ItohN., YoneharaS., IshiiA., YoneharaM., MizushimaS., SameshimaM., HaseA., SetoY., NagataS.1991; The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243
KellyK., DavisP., MitsuyaH., IrvingS., WrightJ., GrassmannR., FleckensteinB., WanoY., GreeneW. C., SiebenlistU.1992; A high proportion of early response genes are constitutively activated in T cells by HTLV-I. Oncogene 7:1463–1470
LiuX., ZacharV., Nørskov-LauritsenN., Aboagye-MathiesenG., ZdravkovicM., Mosborg-PetersenP., DalsgaardA. M., HagerH., EbbesenP.1995; Cell-mediated transmission of human T cell lymphotropic virus type I to human malignant trophoblastic cells results in long-term persistent infection. Journal of General Virology 76:167–173
LosM., Van de CraenM., PenningL. C., SchenkH., WestendorpM., BaeuerleP. A., DrogeW., KrammerP. H., FlersW., Schulze-OsthoffK.1995; Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis. Nature 375:81–83
MiyawakiT., UeharaT., NibuR., TsujiT., YachieA., YoneharaS., TaniguguchiN.1992; Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood. Journal of Immunology 149:3753–3758
NagataK., OhtaniK., NakamuraM., SugamuraK.1989; Activation of endogenous c-fos proto-oncogene expression by human T-cell leukemia virus type I-encoded p40tax protein in the human T-cell line, Jurkat. Journal of Virology 63:3220–3226
NagataniT., MatsuzakiT., IemotoG., KimS., BabaN., MiyamotoH., NakajimaH.1990; Comparative study of cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma: clinical, histopathologic, and immunohistochemical analyses. Cancer 66:2380–2386
NerenbergM., HinrichsS. H., ReynoldsR. K., KhouryG., JayG.1987; The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science 237:1324–1329
NerenbergM. I., MinorT., PriceJ., ErnstD. N., ShinoharaT., SchwarzH.1991; Transgenic thymocytes are refractory to transformation by the human T-cell leukemia virus type I tax gene. Journal of Virology 65:3349–3353
NicolettiI., MiglioratiG., PagliacciM. C., GrignaniF., RiccardiC.1991; A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. Journal of Immunological Methods 139:271–279
RichardsonJ. H., EdwardsA. J., CruickshankJ. K., RudgeP., DalgleishA. G.1990; In vivo cellular tropism of human T-cell leukemia virus type 1. Journal of Virology 64:5682–5687
ShironoK., HattoriT., HataH., NishimuraH., TakatsukiK.1989; Profiles of expression of activated cell antigens on peripheral blood and lymph node cells from different clinical stages of adult T-cell leukemia. Blood 73:1664–1671
SmithM. R., GreeneW. C.1991; Molecular biology of the type I human T-cell leukemia virus (HTLV-I) and adult T-cell leukemia. Journal of Clinical Investigation 87:761–766
SodroskiJ. G., RosenC. A., HaseltineW. A.1984; Trans-acting transcriptional activation of the long terminal repeat of human T lymphotropic viruses in infected cells. Science 225:381–385
SudaT., OkazakiT., NaitoY., YokataN., AraiN., OzakiS., NakaoK., NagataS.1995; Expression of the Fas ligand in cells of T cell lineage. Journal of Immunology 154:3806–3813
TakahashiT., TanakaM., InazawaJ., AbeT., SudaT., NagataS.1994; Human Fas ligand : gene structure, chromosomal location and species specificity. International Immunology 6:1567–1574
TsudaH., HuangR. W., TakatsukiK.1993; Interleukin-2 prevents programmed cell death in adult T-cell leukemia cells. Japanese Journal of Cancer Research 84:431–437
WornerI., MatutesE., BeverleyP. C. L., CatovskyD.1990; The distribution of CD45R, CD29 and CD45RO (UCHL-1) antigens in mature CD4 positive T-cell leukaemias. British Journal of Haematology 74:4399–4444
YamadaT., YamaokaS., GotoT., NakaiM., TsujimotoY., HatanakaM.1994; The human T-cell leukemia virus type I Tax protein induces apoptosis which is blocked by the Bcl-2 protein. Journal of Virology 68:3374–3379
ZacharV., EbbesenP., ThomasR. A., ZacharovaV., GoustinA. S.1994; Basal and Tat-transactivated expression from the human immunodeficiency virus type 1 long terminal repeat in human placental trophoblast rules out promoter-enhancer activation as the partial block to viral replication. Journal of General Virology 75:1461–1468
ZhaoL. J., GiamC. Z.1992; Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction. Proceedings of the National Academy of Sciences, USA 89:7070–7074
ZhengL., FisherG., MillerR. E., PeschonJ., LynchD. H., LenardoM. J.1995; Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377:348–351
ZimmermannK., DobrovnikM., BallaunC., BevecD., HauberJ., BohnleinE.1991; Trans-activation of the HIV-1 LTR by the HIV-1 Tat and HTLV-I Tax proteins is mediated by different cis-acting sequences. Virology 182:874–878