IntroductionHuman T-cell leukemia virus type I (HTLV-I) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and is associated with a variety of inflammatory diseases, including HTLV-I-associated myelopathy/tropical spastic paraparesis. 1-4 HTLV-I Tax is a nuclear phosphoprotein that transactivates viral gene expression by activating cellular transcription factors which, in turn, bind Taxresponsive elements located in the viral long terminal repeat. [5][6][7] Tax has been shown to transactivate cellular gene transcription by acting on proteins such as cAMP response element/activating transcription factor family members, 6,8 serum response factors, 9 and Rel/nuclear factor (NF)-B proteins. [10][11][12] This is thought to contribute to deregulated T-cell proliferation and transformation.The Rel/NF-B proteins in mammalian cells consist of 5 members: p50, p52, p65, c-Rel, and RelB. 13,14 These family members contain a Rel homology domain, a conserved region of approximately 300 amino acids, which is involved in dimerization, DNA binding, and nuclear localization. These proteins form homodimers or heterodimers with other family members and positively regulate a number of cellular genes whose products mediate immune and inflammatory responses as well as lymphoproliferation. In particular, NF-B stimulates production of cytokines, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10, IL-15, tumor necrosis factor (TNF), and interferon (IFN). [13][14][15][16] In resting lymphocytes, NF-B dimers are sequestered in the cytoplasm in an inactive form by association with an inhibitory IB subunit. Following cellular activation, multiple kinase cascades lead to serine phosphorylation of IB by IB kinases (IKKs) and proteosome-mediated degradation, resulting in the release of an active NF-B complex that translocates to the nucleus. In the nucleus, NF-B transactivates genes containing specific consensus sequences in their 5Ј transcriptional regulatory regions. [13][14][15] There is mounting evidence that NF-B dysregulation is important for tumorigenesis. For instance, NF-B activity was shown to protect Epstein-Barr virus (EBV)-infected cells from apoptosis induced by TNF-␣, contributing to increased proliferation of B lymphoblastoid cells. 17 TNF-␣ coactivates the NF-B pathway, which is then able to limit apoptosis, presumably through up-regulation of anti-apoptotic gene transcription. 18 However, in the absence of new protein synthesis, TNF-␣-induced apoptosis proceeds through caspase activation. Indeed, activation of NF-B has been reported to block caspase-8 activity. 18,19 TNF-␣ can also induce apoptosis in EBV-transformed lymphocytes in which NF-B activity is inhibited, and this is associated with decreased expression of the anti-apoptotic bcl-2 and bcl-xl genes. 20 Research indicates the latent membrane protein (LMP)-1 of EBV activates NF-B by associating with TNF receptor (TNFR)-associated factors (TRAFs 1 and 2) and TNFR-associated death domain protein (TRADD). 21,22 NF-B has also been shown in transfection exper...
