DEREGULATION OF CELLULAR IKB KINASES BY HTLV1 TAX

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Human T-cell leukemia virus type 1 (HTLV1) is the etiologic agent of adult T-cell leukemia, an aggressive and often untreatable malignancy of activated CD4+ T lymphocytes. The Tax oncoprotein encoded by HTLV1 potently induces the constitutive nuclear expression of transcription factor NF-kappaB, which exhibits a rapid but transient pattern of biologic activity during normal growth-signal transduction. Although prior investigations have indicated that this viral/host interaction is pivotal for HTLV1-mediated cellular transformation, the pathologic mechanism of Tax action on the host NF-kappaB pathway remains unclear. The applicant's laboratory has recently discovered that HTLV1 Tax triggers NF-kappaB induction via a sequential process involving site-specific phosphorylation, ubiquitination, and degradation of IkappaBalpha, a cytoplasmic inhibitor of NF-kappaB. To initiate this IkappaBalpha targeting function, Tax binds to and persistently activates a multiprotein IkappaB kinase complex (IKK). In sharp contrast, pro-inflammatory cytokines that induce NF-kappaB stimulate a transient rather than persistent IKK response. The central hypothesis of this grant application is that Tax-directed IKK activation is the crucial enzymatic checkpoint leading to IkappaBalpha breakdown and the inappropriate constitutive nuclear import of NF-kappaB in HTLV1-infected T cells. Accordingly, a highly-integrated research program is proposed to elucidate the precise mechanism by which HTLV1. Tax activates the persistent functional expression of IKK catalytic activity. To achieve this overall objective, a combination of immunological, biochemical, and genetic approaches will be used to determine (i) the stability, size distribution, and subunit composition of Tax/IKK complexes in HTLV1-infected T cells, (ii) the molecular mechanism responsible for the formation of these pathologic Tax/IKK complexes, and (iii) the functional role of cellular protein kinases and phosphatases in Tax-directed IKK activation. This proposed investigation will delineate not only how Tax impinges physically on the multiprotein IKK signal transduction apparatus but also the entire functional architecture of this pathologic viral/host interaction at the molecular level. In turn, identification of these important missing links in the Tax/IKK axis will lead to the development of innovative strategies for the therapeutic control of HTLV1-associated diseases.