Adult T-cell leukemia (ATL) is a very aggressive and often fatal T-cell malignancy that is caused by infection of the type I human T-cell leukemia virus (HTLV-I). The HTLV-I encoded Tax protein appears to play a central role in the initiation of this virally induced T-cell malignancy. Tax acts by activating cellular transcription factors, including members of the NF- 1kappaBalpha/Rel family, which in turn induces various cellular genes involved in lymphocyte activation and growth. In resting T cells, NF- kappaB/Rel factors are sequestered m the cytoplasm by various inhibitory proteins including I-kappaB-alpha, a 37 kD protein containing multiple ankyrin-like repeats. HTLV-I Tax expression results in the constitutive nuclear expression of these kappaB-enhancer binding proteins, leading to the deregulated expression the various cellular growth-related genes, which have been proposed to induce the polyclonal T-cell proliferation, a prelude to the establishment of ATL. Our recent studies suggest that Tax activation of NF-kappaB is associated with the phosphorylation and degradation of I-kappaB-alpha and the activated nuclear NF-kappaB seems, together with other yet to be identified transcriptional enhancers or silencers, to mediate the Tax-induced transcriptional induction of the c- rel proto-oncogene. We have further observed that these Tax-induced cellular events can be blocked by various inhibitors of cellular signal transduction. Together, these results raise the possibility that Tax may induce a specific cellular signal transduction pathway leading to a cascade of both cytoplasmic and nuclear reactions with phosphorylation of IkBa serving as a molecular trigger. This specific action of Tax results in the nuclear expression of both NF-kB and c-Rel. Based on these results, the overall objective of this grant proposal is a fundamental understanding of the Tax-mediated NF-kappaB/Rel induction signaling pathway. To approach this overall objective, a set of biochemical studies will be undertaken to precisely map the sites of Tax-induced phosphorylation within I-kappaB-alpha. In turn, site-directed mutations will be sequentially introduced into these sites to examine the functional significance of these phosphorylation events on Tax-mediated I-kappaB- alpha degradation. In conjunction with these site-directed mutagenesis, progressive deletional analyses will also be performed to completely define the sequences within I-kappaB-alpha that are required for protease attack. To explore the Tax-mediated signaling pathway, different strategies will be used to identify and characterize the cellular molecular components, including I-kappaB-alpha-specific kinases and the more proximal signaling molecules, involved in the Tax-mediated activation of NF-kappaB/Rel. Finally, the precise mechanism of Tax-induced transcriptional induction of c-rel gene will be explored by isolation and functional analyses of the human c-rel gene promoter.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068471-04
Application #
2712745
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Cole, John S
Project Start
1995-08-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Harhaj, Nicole S; Sun, Shao-Cong; Harhaj, Edward W (2007) Activation of NF-kappa B by the human T cell leukemia virus type I Tax oncoprotein is associated with ubiquitin-dependent relocalization of I kappa B kinase. J Biol Chem 282:4185-92
Wu, Xuefeng; Sun, Shao-Cong (2007) Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK. EMBO Rep 8:510-5
Babu, Geetha; Waterfield, Michael; Chang, Mikyoung et al. (2006) Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-I-transformed T cells. J Biol Chem 281:14041-7
Harhaj, Edward W; Harhaj, Nicole S; Grant, Christian et al. (2005) Human T cell leukemia virus type I Tax activates CD40 gene expression via the NF-kappa B pathway. Virology 333:145-58
Sun, Shao-Cong; Yamaoka, Shoji (2005) Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene 24:5952-64
Cvijic, Mary Ellen; Xiao, Gutian; Sun, Shao-Cong (2003) Study of T-cell signaling by somatic cell mutagenesis and complementation cloning. J Immunol Methods 278:293-304
Sun, Shao-Cong; Xiao, Gutian (2003) Deregulation of NF-kappaB and its upstream kinases in cancer. Cancer Metastasis Rev 22:405-22
Waterfield, Michael R; Zhang, Minying; Norman, Lourdes P et al. (2003) NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol Cell 11:685-94
Xiao, G; Cvijic, M E; Fong, A et al. (2001) Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: evidence for the involvement of IKKalpha. EMBO J 20:6805-15
Rivera-Walsh, I; Waterfield, M; Xiao, G et al. (2001) NF-kappaB signaling pathway governs TRAIL gene expression and human T-cell leukemia virus-I Tax-induced T-cell death. J Biol Chem 276:40385-8

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