title: Evidence in support of a role for human T-cell leukemia virus type I Tax in activating NF-kappa B via stimulation of signaling pathways.
abstract: The human T-cell leukemia virus type I Tax protein activates NF-kappa B transcription factors from preformed cytoplasmic pools, including those pools that are retained by the I kappa B-alpha inhibitory protein. Degradation of I kappa B-alpha is enhanced by Tax, resulting in the liberation of some NF-kappa B, which then translocates into the nucleus. Here we have investigated the mechanism by which Tax causes degradation of I kappa B-alpha. Two I kappa B-alpha mutants defective in extracellular signal-induced degradation of I kappa B-alpha also blocked Tax-mediated kappa B-dependent transactivation when cotransfected into Jurkat T cells. Cotransfected wild-type I kappa B-alpha or an irrelevant mutant did not significantly effect transactivation induced by Tax. The signal-defective I kappa B-alpha proteins are mutated at either of two closely spaced serines in the N terminus of the protein (Ser32 and Ser36). In wild-type I kappa B-alpha, one or both of these serines are inducibly phosphorylated with extracellular stimuli, and such phosphorylation appears necessary for subsequent degradation and thus activation of NF-kappa B. These results suggest that Tax triggers I kappa B-alpha degradation and thus NF-kappa B activation by a mechanism that converges with that induced by extracellular stimulation such as phorbol 12-myristate 13-acetate/ionomycin or tumor necrosis factor alpha. A role for Tax in activating signal transduction pathways upstream of I kappa B-alpha is implied.
authors.affiliation: Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1876, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kanno
authors.forename: K
authors.initials: K
authors.lastname: Brown
authors.forename: U
authors.initials: U
authors.lastname: Siebenlist
mesh_terms: D005786:Gene Expression Regulation / Q000187:drug effects; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051841:Transcription Factor RelB; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016356:Gene Products, tax; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB; D012694:Serine; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate