Human T cell leukemia virus type I is a human retrovirus that is the causative agent of the aggressive and fatal adult T cell leukemia (ATL). The viral protein Tax is essential for the transformation of human T cells. Tax induces aberrant expression of growth-related cellular genes by activation of host transcription factors, most importantly the NF-kB family of enhancer binding proteins. Tax triggers activation of IkB kinases (IKKs) that phosphorylate and lead to degradation of IkB, the cytoplasmic inhibitor of NF-kB. This proposal aims to explore the molecular mechanisms by which Tax triggers NF-kB signaling. In the first specific aim, various biochemical approaches will be used to determine the mechanisms by which Tax induces IKK activation. Coimmunoprecipitation (co-IP) studies will examine whether physical interaction between Tax and IKKs is essential for Tax-mediated IKK activation. Co-IP and mammalian two-hybrid assays will evaluate whether Tax promotes the interaction of IKKs with the NF-kB inducing kinase (NIK), an IKK-upstream kinase. In vitro kinase assays will examine whether Tax influences IKK opposing phosphatases.
The second aim proposes to identify and clone novel cellular factors participating in Tax-mediated NF-kB signal transduction by isolating Tax-associating proteins by biochemical and genetic (yeast two-hybrid) approaches and evaluating their effects on IKK activation. """"""""Expression cloning"""""""" will also be used to clone signaling factors involved in Tax activation of NF-kB. Further understanding of Tax-induced NF-kB activation will provide important insights into T-cell transformation and development of ATL.
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| 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 |
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