The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphornas
The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphornas
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DOI：
10.1073/pnas.0507809103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Ratner, Lee
中科院分区：
文献类型：
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作者：
Bernal-Mizrachi, Leon;Lovly, Christine M.;Ratner, Lee
NF-κ B通路与包括非霍奇金淋巴瘤和霍奇金淋巴瘤在内的几种淋巴系统恶性肿瘤的发生有关。然而，抗凋亡功能和负责通过每个NF-κ B通路的信号传导的机制仍有待阐明。在目前的研究中，发现具有组成性活性NF-κ B的淋巴瘤细胞系对外源性和内源性凋亡途径的诱导剂具有抗性。对细胞死亡的抵抗来自于细胞凋亡级联反应早期和晚期的阻断。几种NF-κ B靶基因在这些细胞系中过表达，包括Bcl-xL、Fas相关死亡结构域样IL-1 β转化酶抑制蛋白、细胞凋亡抑制因子和X凋亡抑制因子。用表达稳定形式NF-κ B抑制剂（I κ B）的小干扰RNA或腺病毒抑制经典或非经典NF-κ B通路，可增强对凋亡诱导剂的敏感性，并导致Bcl-xL或Fas相关死亡结构域样IL-1 β转化酶抑制剂蛋白、细胞凋亡抑制剂和X凋亡抑制剂水平降低。这些发现表明NF-κ B途径在介导细胞凋亡抵抗中发挥重要作用，并且独特的抗细胞凋亡下游靶基因谱负责这种效应。
The NF-kappa B pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-kappa B pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-kappa B were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-kappa B target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1 beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-kappa B pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-kappa B (I kappa B) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1 beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-kappa B pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.