Brown K, Park S, Kanno T, Franzoso G, Siebenlist U
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2532-6. doi: 10.1073/pnas.90.6.2532.
The NK-kappa B transcription factor complex is sequestered in the cytoplasm by the inhibitory protein I kappa B-alpha (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-kappa B nuclear localization and transactivation of its target genes. It is demonstrated here with human T lymphocytes and monocytes that different stimuli, including tumor necrosis factor alpha and phorbol 12-myristate 13-acetate, cause rapid degradation of I kappa B-alpha, with concomitant activation of NF-kappa B, followed by a dramatic increase in I kappa B-alpha mRNA and protein synthesis. Transfection studies reveal that the I kappa B-alpha mRNA and the encoded protein are potently induced by NF-kappa B and by homodimers of p65 and of c-Rel. We propose a model in which NF-kappa B and I kappa B-alpha mutually regulate each other in a cycle: saturating amounts of the inhibitory I kappa B-alpha protein are destroyed upon stimulation, allowing rapid activation of NF-kappa B. Subsequently, I kappa B-alpha mRNA and protein levels are quickly induced by the activated NF-kappa B. This resurgence of I kappa B-alpha protein acts to restore an equilibrium in which NF-kappa B is again inhibited.
核因子-κB转录因子复合物被抑制蛋白IκB-α（MAD-3）隔离于细胞质中。多种细胞刺激通过很大程度上未知的机制解除这种抑制，导致核因子-κB定位于细胞核并激活其靶基因。本文在人T淋巴细胞和单核细胞中证明，包括肿瘤坏死因子α和佛波酯12-肉豆蔻酸酯13-乙酸酯在内的不同刺激会导致IκB-α迅速降解，同时核因子-κB被激活，随后IκB-αmRNA和蛋白质合成显著增加。转染研究表明，IκB-αmRNA和编码的蛋白质受到核因子-κB以及p65和c-Rel同源二聚体的强烈诱导。我们提出了一个模型，其中核因子-κB和IκB-α在一个循环中相互调节：刺激时，抑制性IκB-α蛋白的饱和量被破坏，使得核因子-κB迅速激活。随后，活化的核因子-κB迅速诱导IκB-αmRNA和蛋白质水平升高。IκB-α蛋白的这种重新出现起到恢复平衡的作用，在此平衡中核因子-κB再次受到抑制。
