Kinetic analysis of human T-cell leukemia virus type I Tax-mediated activation of NF-kappa B.
The human T-cell leukemia virus type I (HTLV-I) Tax protein induces the expression of cellular genes, at least in part, by activating the endogenous NF-kappa B transcription factors. Induced expression of cellular genes is thought to be important for transformation of T cells to continued growth, a prelude to the establishment of adult T-cell leukemia. However, neither underlying mechanisms nor kinetics of the Tax-mediated activation of NF-kappa B are understood. We have analyzed a permanently transfected Jurkat T-cell line in which the expression of Tax is entirely dependent on addition of heavy metals. The initial NF-kappa B binding activity seen after induction of Tax is due almost exclusively to p50/p65 heterodimers. At later times, NF-kappa B complexes containing c-Rel and/or p52 accumulate. The early activation of p50/p65 complexes is a posttranslational event, since neither mRNA nor protein levels of NF-kappa B subunits had increased at that time. We demonstrate for the first time a Tax-induced proteolytic degradation of the NF-kappa B inhibitor, I kappa B-alpha, which may trigger the initial nuclear translocation of NF-kappa B. As nuclear NF-kappa B rapidly and potently stimulates resynthesis of I kappa B-alpha, the steady-state level of I kappa B-alpha does not significantly change. Thus, the dramatic Tax-induced increase in the I kappa B-alpha turnover may continually weaken inhibition and activate NF-kappa B. Additional, distinct actions of Tax may contribute further to the high levels of NF-kappa B activity seen.
Kanno
T
T
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Brown
K
K
Franzoso
G
G
Siebenlist
U
U
D002712:Chlorides / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D013601:T-Lymphocytes / Q000382:microbiology*; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D017967:Zinc Compounds / Q000494:pharmacology
D002712:Chlorides; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D017967:Zinc Compounds; D000072000:NF-KappaB Inhibitor alpha; C016837:zinc chloride; D010450:Endopeptidases