Deregulation of Cellular IkB Kinases by HTLV1 Tax

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DESCRIPTION (provided by applicant): Infection with human T-cell leukemia virus type 1 (HTLV1) can lead to inappropriate growth-signal transduction, the loss of cell cycle control, and the development of an aggressive malignancy manifested as adult T-cell leukemia (ATL). Acquisition of the transformed phenotype is contingent upon the interplay of the HTLV1 Tax oncoprotein with transcription factor NF-kB, which normally helps initiate the genetic programs for inflammation and immunity. In contrast to the transient pattern of NF-kB action elicited by proinflammatory mediators such as tumor necrosis factor-alpha (TNF), NF-kB is constitutively active in cells expressing Tax. Tax hijacks this host signaling pathway by forming stable complexes with IKK, a TNF-inducible IkB kinase. In turn, Tax converts IKK into a constitutively active kinase that earmarks cytoplasmic inhibitors of NF-kB for proteolytic destruction. This is an application for continuation of a project to dissect the pathologic mechanism of Tax action on IKK. Studies conducted during the present funding period indicate that this mechanism involves Tax-induced phosphorylation and ubiquitination of IKK. These two post-translational modifications are biochemically coupled. Moreover, Tax-dependent conjugation of ubiquitin (Ub) to IKK is disrupted in cells expressing YopJ, a Ub-like protein protease that inhibits NF-kB signal transduction. The central hypothesis under investigation is that IKK ubiquitination plays a critical role in the regulation of both normal and pathophysiologic NF-kB signaling. To test the central hypothesis, experiments are proposed to determine (i) the Ub acceptor sites in IKK that are modified in response to the Tax oncoprotein and proinflammatory agonists, (ii) the biochemical mechanism and function of IKK ubiquitination in NF-kB signal transduction, and (iii) the in vivo role of IKK ubiquitination in Tax-associated disease and immunobiology. Results from these studies may facilitate the identification of new molecular targets involved in IKK ubiquitination for therapeutic intervention in cancer, inflammation, and autoimmunity. The workscope of this application is responsive to Program Announcement PA-03-145, entitled "Ubiquitin and ubiquitin-like modifications regulating disease processes".