A p105-based inhibitor broadly represses NF-κB activities
A p105-based inhibitor broadly represses NF-κB activities
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DOI：
10.1074/jbc.m312572200
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发表时间：
2004-03-26
影响因子：
4.8
通讯作者：
Lin, L
中科院分区：
文献类型：
--
作者：
Fu, DX;Kobayashi, M;Lin, L
基于IkappaBalpha的核因子-kappaB超级抑制子(Sr)已被广泛用于研究受核因子-kappaB转录因子调控的基因。IkappaBalpha(Sr)对核因子-kappaB的抑制也促进了肿瘤坏死因子α诱导的细胞凋亡。然而，IkappaBalpha主要针对包含relA和c-rel的复合体，而其他NF-kappaB/rel蛋白复合体，如p50和p52同源二聚体，以及RelB异源二聚体不受抑制。由于这些非典型的核因子-kappaB复合体也有助于基因调控，并在病理条件下被激活，因此广泛抑制所有的核因子-kappaB具有重要的药理学和临床意义。我们已经设计、产生并测试了一个基于p105的核转录因子-kappaB超级阻遏因子。我们发现，p105(Sr)不再产生p50并经历信号诱导的降解，它有效地抑制了所有的NF-kappaB活性。此外，我们还证明，p105(Sr)显著增强肿瘤坏死因子α介导的对p50同源二聚体活性升高的MT1/2皮肤乳头状瘤细胞的杀伤作用。我们的结果表明，p105(Sr)是一种范围更广且有效的核因子-kappaB超抑制因子，可用于以非规范的核因子-kappaB活性为主或多种核因子-kappaB活性被激活的细胞。
An IkappaBalpha-based NF-kappaB super repressor (sr) has been used widely for studying genes regulated by NF-kappaB transcription factors. Repression of NF-kappaB by IkappaBalpha(sr) also facilitates tumor necrosis factor alpha-induced apoptosis in the cell. However, IkappaBalpha primarily targets RelA and c-Rel-containing complexes, leaving other NF-kappaB/Rel protein complexes, such as p50 and p52 homodimers, and RelB heterodimers uninhibited. Because these atypical NF-kappaB complexes also contribute to gene regulation and are activated in pathological conditions, broad inhibition of all NF-kappaB species is of significant pharmacological and clinical interests. We have designed, generated, and tested a p105-based NF-kappaB super repressor. We showed that p105(sr), which no longer generates p50 and undergoes signal-induced degradation, effectively inhibits all NF-kappaB activities. In addition, we also demonstrated that p105(sr) significantly enhances tumor necrosis factor alpha-mediated killing of MT1/2 skin papilloma cells where p50 homodimer activity is elevated. Our results suggest that p105(sr) is a broader range and effective NF-kappaB super repressor and can potentially be used in cells where a noncanonical NF-kappaB activity is dominant or multiple NF-kappaB activities are activated.