MUTUAL REGULATION OF THE TRANSCRIPTIONAL ACTIVATOR NF-KAPPA-B AND ITS INHIBITOR, I-KAPPA-B-ALPHA
MUTUAL REGULATION OF THE TRANSCRIPTIONAL ACTIVATOR NF-KAPPA-B AND ITS INHIBITOR, I-KAPPA-B-ALPHA
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DOI：
10.1073/pnas.90.6.2532
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发表时间：
1993-03-15
影响因子：
11.1
通讯作者：
SIEBENLIST, U
中科院分区：
文献类型：
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作者：
BROWN, K;PARK, S;SIEBENLIST, U
NF-kappaB转录因子复合物通过抑制蛋白ikappab - α (MAD-3)隔离在细胞质中。各种细胞刺激通过很大程度上未知的机制缓解这种抑制，导致NF-kappaB核定位和其靶基因的反激活。研究表明，在人T淋巴细胞和单核细胞中，不同的刺激，包括肿瘤坏死因子α和12-肉芽酸酯13-乙酸磷，会导致ikappab - α的快速降解，同时NF-kappaB被激活，随后ikappab - α mRNA和蛋白合成急剧增加。转染研究表明，ikappab - α mRNA和编码蛋白可被NF-kappaB和p65和c-Rel的同型二聚体有效诱导。我们提出了一个NF-kappaB和ikappab - α在一个循环中相互调节的模型：抑制ikappab - α蛋白的饱和量在刺激时被破坏，允许NF-kappaB快速激活。随后，活化的NF-kappaB快速诱导ikappab - α mRNA和蛋白水平。ikappab - α蛋白的复苏恢复了NF-kappaB再次被抑制的平衡。
The NF-kappaB transcription factor complex is sequestered in the cytoplasm by the inhibitory protein IkappaB-alpha (MAD-3). Various cellular stimuli relieve this inhibition by mechanisms largely unknown, leading to NF-kappaB 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 IkappaB-alpha, with concomitant activation of NF-kappaB, followed by a dramatic increase in IkappaB-alpha mRNA and protein synthesis. Transfection studies reveal that the IkappaB-alpha mRNA and the encoded protein are potently induced by NF-kappaB and by homodimers of p65 and of c-Rel. We propose a model in which NF-kappaB and IkappaB-alpha mutually regulate each other in a cycle: saturating amounts of the inhibitory IkappaB-alpha protein are destroyed upon stimulation, allowing rapid activation of NF-kappaB. Subsequently, IkappaB-alpha mRNA and protein levels are quickly induced by the activated NF-kappaB. This resurgence of IkappaB-alpha protein acts to restore an equilibrium in which NF-kappaB is again inhibited.