HTLV-I Tax Induces Cellular Proteins that Activate the κB Element in the IL-2 Receptor α Gene

Abstract

Jurkat T cell lines constitutively expressing Tax, the 40-kilodalton transactivator protein of human T lymphotropic virus type I (HTLV-I), were used to investigate the mechanism by which this viral product deregulates the expression of the interleukin-2 receptor alpha gene (IL-2R alpha, Tac). Transfection of deleted forms of the IL-2R alpha promoter and in vitro DNA-binding studies revealed that a 12-base pair promoter segment, which has homology with the binding site for NF-kappa B, was required for Tax-induced activation of the IL-2R alpha promoter in vivo. An 18-base pair oligonucleotide containing this kappa B-like regulatory element proved sufficient to confer Tax inducibility upon a heterologous promoter. DNA affinity precipitation assays showed that Tax, like mitogenic stimuli, induced the expression of the 86-kilodalton cellular protein HIVEN86A, which specifically binds to the IL-2R alpha kappa B element in vitro. Furthermore, DNA/protein cross-linking studies revealed that several polypeptides interact with this sequence motif. Thus, the deregulation of IL-2R alpha gene expression encountered in HTLV-I leukemias appears to involve Tax activation of one or more cellular proteins that are normally induced by mitogens and that directly contribute to transcriptional activation of this receptor gene.

The C-terminus of the HTLV-1 Tax oncoprotein mediates interaction with the PDZ domain of cellular proteins

“…The activity of these proteins, which activate expression of genes participating to the immune and in¯ammatory responses, is regulated mainly through cytoplasmic retention. Expression of Tax in lymphocytes induces a permanent presence of the NF-kB/Rel factors in the nucleus (Ballard et al, 1988;Leung and Nabel, 1988;Ruben et al, 1988). This e ect is likely to result from an activation of the proteolytic processing of the inhibitory molecules IkB-a (Lacoste et al, 1995), IkB-b (Good and Sun, 1996) and NF-kB1 p105 .…”

An interaction between the DNA-binding domains of RelA(p65) and Sp1 mediates human immunodeficiency virus gene activation.

“…In most cell types, NF-KB exists as a cytoplasmic complex consisting of -50-and 65-kDa subunits bound to an inhibitory protein termed IKB (3-5, 74, 75). Activators of NF-KB, which include naturally occurring cytokines such as tumor necrosis factor alpha and interleukin-1 (50), phorbol esters (65), and the human T-cell leukemia virus type I Tax protein (6,41), induce its nuclear localization through dissociation from lKB (3,4,7,21).…”

Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-κB pathway

“…This is the case of the genes coding for IL-2R, TNF-a, the proto-oncogene c-myc, antiapoptotic proteins and caspase inhibitors as well as for p53 inactivation. 17,19,70 Overall, Taxinduced activation of the NF-kB pathway is critical for ATL Figure 2 Molecular mechanisms of Tax-induced activation of the NF-kB pathway. Tax acts at multiple levels to initiate and maintain NF-kB activation: (1) Tax dimers activate IKK by interacting with the noncatalytic subunit IKK-g, facilitating the recruitment of Tax to the catalytic subunits IKK-a and IKK-b.…”