A human T-cell leukemia virus Tax variant incapable of activating NF-kappaB retains its immortalizing potential for primary T-lymphocytes.
The human T-cell leukemia virus type 1 (HTLV-1) transactivator (Tax) has been shown to interfere with regulated cellular proliferation. Many studies have focused on the ability of Tax to transform rodent fibroblasts; however, none has defined the molecular requirements for Tax transformation of human lymphoid cells. We show here that tax induces permanent growth of human primary T-lymphocytes by using a transformation/immortalization defective rhadinovirus vector. The cells phenotypically resemble HTLV-immortalized lymphocytes and contain episomally persisting recombinant rhadinoviral sequences, which stably express functional Tax protein. As Tax can activate major cellular signal transducing pathways including NF-kappaB and cAMP-responsive element binding protein (CREB), we asked for the relevance of these routes in the immortalization of human lymphocytes. By using Tax mutants that either activate exclusively CREB/activating transcription factor or are defective in activating this signaling pathway, we delineated that Tax can induce immortalization of primary human T-lymphocytes through a mechanism independent of NF-kappaB activation.
Rosin
O
O
Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Federal Republic of Germany.
Koch
C
C
Schmitt
I
I
Semmes
O J
OJ
Jeang
K T
KT
Grassmann
R
R
D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D016356:Gene Products, tax / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
D016356:Gene Products, tax; D016328:NF-kappa B; D015375:Receptors, Interleukin-2