Segregation of NF-κB activation through NEMO/IKKγ by Tax and TNFα:: implications for stimulus-specific interruption of oncogenic signaling
Segregation of NF-κB activation through NEMO/IKKγ by Tax and TNFα:: implications for stimulus-specific interruption of oncogenic signaling
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DOI：
10.1038/sj.onc.1207058
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发表时间：
2003-12-04
期刊：
影响因子：
8
通讯作者：
Jeang, KT
中科院分区：
文献类型：
--
作者：
Iha, H;Kibler, KV;Jeang, KT
核因子-κ B必需调节剂（NEMO），也称为IKK γ，已被提议作为I-κ B激酶（IKK）复合物的“通用”适配器，用于刺激如促炎细胞因子、微生物和HTLV-1 Tax癌蛋白。目前，还不清楚通过NEMO激活NF-κ B的许多信号是否相同或不同地收敛。我们采取了两种方法来回答这个问题。首先，我们产生并靶向细胞内三个NEMO特异性单克隆抗体（mAb）。这些mAb产生两种不同的细胞内NF-κ B抑制谱，将TNF α与Tax活化分离。第二，使用NEMO敲除小鼠成纤维细胞和10个NEMO突变体，我们发现不同的区域反式发挥功能，以补充或抑制TNF α，IL-1 β或NF-κ B的Tax激活。例如，NEMO（1-245个氨基酸）支持Tax介导的NF-κ B活化，但不提供TNF α或IL-1 β信号传导。总之，我们的研究结果表明，虽然NEMO“普遍”适应许多NF-κ B激活剂，它可能是通过可分离的结构域。我们提供了第一个证据表明，选择性靶向NEMO可以消除致癌Tax信号，而不影响用于正常细胞代谢的信号。
Nuclear factor-kappaB essential modulator (NEMO), also called IKKgamma, has been proposed as a 'universal' adaptor of the I-kappaB kinase (IKK) complex for stimuli such as proinflammatory cytokines, microbes, and the HTLV-I Tax oncoprotein. Currently, it remains unclear whether the many signals that activate NF-kappaB through NEMO converge identically or differently. We have adopted two approaches to answer this question. First, we generated and targeted intracellularly three NEMO-specific monoclonal antibodies (mAbs). These mAbs produced two distinct intracellular NF-kappaB inhibition profiles segregating TNFalpha from Tax activation. Second, using NEMO knockout mouse fibroblasts and 10 NEMO mutants, we found that different regions function in trans either to complement or to inhibit dominantly TNFalpha, IL-1beta, or Tax activation of NF-kappaB. For instance, NEMO (1-245 amino acids) supported Tax-mediated NF-kappaB activation, but did not serve TNFalpha- or IL-1beta signaling. Altogether, our findings indicate that while NEMO 'universally' adapts numerous NF-kappaB activators, it may do so through separable domains. We provide the first evidence that selective targeting of NEMO can abrogate oncogenic Tax signaling without affecting signals used for normal cellular metabolism.