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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Impaired degradation of inhibitory subunit of NF-kappa B (I kappa B) and beta-catenin as a result of targeted disruption of the beta-TrCP1 gene
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Impaired degradation of inhibitory subunit of NF-kappa B (I kappa B) and beta-catenin as a result of targeted disruption of the beta-TrCP1 gene

机译：由于靶向破坏β-TrCP1基因，导致NF-κB（I kappa B）和β-catenin抑制亚基的降解受损

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摘要

beta-TrCP1 (also known as Fbw1a or FWD1) is the F-box protein component of an Skp1/Cul1/F-box (SCF)-type ubiquitin ligase complex. Although biochemical studies have suggested that beta-TrCP1 targets inhibitory subunit of NF-kappaB (IkappaB) proteins and beta-catenin for ubiquitylation, the physiological role of beta-TrCP1 in mammals has remained unclear. We have now generated mice deficient in beta-TrCP1 and shown that the degradation of IkappaBalpha and IkappaBbeta is reproducibly, but not completely, impaired in the cells of these animals. The nuclear translocation and DNA-binding activity of NF-kappaB as well as the ability of this transcription factor to activate a luciferase reporter gene were also inhibited in beta-TrCP1(-1-) cells compared with those apparent in wild-type cells. The subcellular localization of beta-catenin was altered markedly in beta-TrCP1(-/-) cells. Furthermore, the rate of proliferation was reduced and both cell size and the percentage of polyploid cells were increased in embryonic fibroblasts derived from beta-TrCP1(-1-) mice pared with the corresponding wild-type cells. These results suggest that beta-TrCPI contributes to, but is not absolutely required for, the degradation Of IkappaB and beta-catenin and the consequent regulation of the NF-kappaB and Wnt signaling pathways, respectively. In addition, they implicate beta-TrCP1 in the maintenance of ploidy during cell-cycle progression. [References: 42]
机译：beta-TrCP1（也称为Fbw1a或FWD1）是Skp1 / Cul1 / F-box（SCF）型泛素连接酶复合物的F-box蛋白成分。尽管生化研究表明，β-TrCP1靶向抑制NF-κB（IkappaB）蛋白和β-连环蛋白的泛素化作用，但在哺乳动物中，β-TrCP1的生理作用仍不清楚。我们现在已经生成了缺乏β-TrCP1的小鼠，并表明IkappaBalpha和IkappaBbeta的降解在这些动物的细胞中可再现但并非完全受损。与野生型细胞相比，β-TrCP1（-1-）细胞中NF-κB的核易位和DNA结合活性以及该转录因子激活萤光素酶报告基因的能力也受到抑制。在β-TrCP1（-/-）细胞中，β-catenin的亚细胞定位发生了明显变化。此外，在与相应的野生型细胞配对的β-TrCP1（-1-）小鼠胚胎成纤维细胞中，增殖速率降低，细胞大小和多倍体细胞百分比均增加。这些结果表明，β-TrCPI分别促成但不是IkappaB和β-catenin的降解以及随后对NF-kappaB和Wnt信号通路的调节所必需。此外，它们在细胞周期进程中暗示β-TrCP1维持倍性。 [参考：42]

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