Kanno T, Brown K, Franzoso G, Siebenlist U
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Mol Cell Biol. 1994 Oct;14(10):6443-51. doi: 10.1128/mcb.14.10.6443-6451.1994.
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.
人类I型T细胞白血病病毒（HTLV-I）的Tax蛋白至少部分地通过激活内源性核因子κB（NF-κB）转录因子来诱导细胞基因的表达。细胞基因的诱导表达被认为对于T细胞转化为持续生长很重要，而持续生长是成人T细胞白血病发生的前奏。然而，Tax介导的NF-κB激活的潜在机制和动力学都还不清楚。我们分析了一个永久转染的Jurkat T细胞系，其中Tax的表达完全依赖于重金属的添加。诱导Tax表达后最初观察到的NF-κB结合活性几乎完全归因于p50/p65异二聚体。在随后的时间里，含有c-Rel和/或p52的NF-κB复合物会积累。p50/p65复合物的早期激活是一个翻译后事件，因为此时NF-κB亚基的mRNA和蛋白质水平都没有增加。我们首次证明Tax诱导了NF-κB抑制剂IκB-α的蛋白水解降解，这可能触发了NF-κB的初始核转位。由于核内的NF-κB迅速而有力地刺激IκB-α的重新合成，IκB-α的稳态水平没有显著变化。因此，Tax诱导的IκB-α周转的显著增加可能会持续削弱抑制作用并激活NF-κB。Tax的其他不同作用可能进一步导致了所观察到的高水平的NF-κB活性。
