...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Compensatory Ikkα Activation Of Classical Nf-κb Signaling During Ikkβ Inhibition Identified By An Rna Interference Sensitization Screen
【24h】

Compensatory Ikkα Activation Of Classical Nf-κb Signaling During Ikkβ Inhibition Identified By An Rna Interference Sensitization Screen

机译：Rna干扰敏化屏幕识别的Ikkβ抑制过程中经典Nf-κb信号的代偿性Ikkα激活

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

A subtype of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like (ABC) DLBCL, depends on constitutive nuclear factor-κB (NF-κB) signaling for survival. Small molecule inhibitors of IκB kinase β (IKKβ), a key regulator of the NF-κB pathway, kill ABC DLBCL cells and hold promise for the treatment of this lymphoma type. We conducted an RNA interference genetic screen to investigate potential mechanisms of resistance of ABC DLBCL cells to IKKβ inhibitors. We screened a library of small hairpin RNAs (shRNAs) targeting 500 protein kinases for shRNAs that would increase the killing of an ABC DLBCL cell line in the presence of a small molecule IKKβ inhibitor. Two independent shRNAs targeting IKKα synergized with the IKKβ inhibitor to kill three different ABC DLBCL cell lines but were not toxic by themselves. Surprisingly, IKKα shRNAs blocked the classical rather than the alternative NF-κB pathway in ABC DLBCL cells, as judged by inhibition of IκBα phosphorylation. IKKα shRNA toxicity was reversed by coexpression of wild-type but not kinase inactive forms of IKKα, suggesting that IKKα may directly phosphorylate Iκ-Bα under conditions of IKKβ inhibition. In models of physiologic NF-κB pathway activation by CARD11 or tumor necrosis factor-α, compensatory IKKα activity was also observed with IKKβ inhibition. These results suggest that therapy for ABC DLBCL may be improved by targeting both IKKα and IKKβ, possibly through CARD11 inhibition.
机译：弥漫性大B细胞淋巴瘤（DLBCL）的一种亚型，称为活化B细胞样（ABC）DLBCL，取决于生存的组成性核因子-κB（NF-κB）信号传导。 IκB激酶β（IKKβ）的小分子抑制剂是NF-κB通路的关键调节剂，可杀死ABC DLBCL细胞，并有望用于治疗这种淋巴瘤类型。我们进行了RNA干扰基因筛选，以研究ABC DLBCL细胞对IKKβ抑制剂产生抗性的潜在机制。我们筛选了靶向500种蛋白激酶的小发夹RNA（shRNA）库，以寻找可在小分子IKKβ抑制剂存在下增加ABC DLBCL细胞系杀伤力的shRNA。靶向IKKα的两个独立的shRNA与IKKβ抑制剂协同作用，杀死了三种不同的ABC DLBCL细胞系，但它们自身没有毒性。出乎意料的是，通过抑制IκBα磷酸化判断，IKKαshRNA阻断了ABC DLBCL细胞中的经典而非替代性NF-κB途径。 IKKαshRNA毒性可通过野生型但非激酶非活性形式的IKKα的共表达而逆转，表明IKKα可能在IKKβ抑制的条件下直接磷酸化Iκ-Bα。在由CARD11或肿瘤坏死因子-α激活的生理性NF-κB途径模型中，还观察到具有IKKβ抑制作用的代偿性IKKα活性。这些结果表明，通过同时靶向IKKα和IKKβ，可能可以通过CARD11抑制来改善ABC DLBCL的治疗。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号