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首页> 外文期刊>Oncogene >Role of NF-|[kappa]|B signaling in hepatocyte growth factor|[sol]|scatter factor-mediated cell protection
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Role of NF-|[kappa]|B signaling in hepatocyte growth factor|[sol]|scatter factor-mediated cell protection

机译：NF- | B信号在肝细胞生长因子|β-散射因子介导的细胞保护中的作用

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The cytokine scatter factor/hepatocyte growth factor (HGF/SF) protects epithelial, carcinoma, and other cell types against cytotoxicity and apoptosis induced by DNA-damaging agents such as ionizing radiation and adriamycin (ADR, a topoisomerase II inhibitor). We investigated the role of nuclear factor kappa B (NF-B) signaling in HGF/SF-mediated protection of human prostate cancer (DU-145) and Madin–Darby canine kidney (MDCK) epithelial cells against ADR. HGF/SF caused the rapid nuclear translocation of the p65 (RelA) subunit of NF-B associated with the transient loss of the inhibitory subunit IB-. Exposure to HGF/SF caused the activation of an NF-B luciferase reporter that was blocked or attenuated by the expression of a mutant 'super-repressor' IB-. Electrophoretic mobility shift assay supershift assays revealed that HGF/SF treatment induced the transient binding of various NF-B family proteins (p65, p50, c-Rel, and RelB) with radiolabeled NF-B-binding oligonucleotides. The HGF/SF-mediated protection of DU-145 and MDCK cells against ADR (demonstrated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays) was abrogated by the IB- super-repressor. The ability of HGF/SF to activate NF-B signaling was dependent on c-Akt Pak1 (p21-associated kinase-1) signaling (with Pak1 downstream of c-Akt) and was inhibited by the tumor suppressor PTEN (phosphatase and tensin homolog). Inhibitors of phosphatidylinositol-3'-kinase and Src family kinases significantly inhibited HGF/SF-mediated activation of NF-B, while inhibitors of MEK, protein kinase C, and p70 S6 kinase had a modest effect or no effect on NF-B activity. HGF/SF induced the expression of several known NF-B target genes (cIAP-1 (cellular inhibitor of apoptosis-1), cIAP-2, and TRAF-2 (TNF receptor-associated factor-2)) in an NF-B-dependent manner; HGF/SF blocked the inhibition of expression of these genes by ADR. Experimental manipulation of expression of these genes suggests that they (particularly TRAF-2 and cIAP-2) contribute to the protection against ADR by HGF/SF. These findings suggest that HGF/SF activates NF-B through a c-Akt Pak1 signaling pathway that is also dependent on Src, and that NF-B contributes to HGF/SF-mediated protection against ADR.
机译：细胞因子散射因子/肝细胞生长因子（HGF / SF）保护上皮，癌和其他细胞类型免受DNA损伤剂等的细胞毒性和细胞凋亡，例如电离辐射和adriamycin（ADR，拓扑异构酶II抑制剂）。我们调查了核因子Kappa B（NF-B）信号传导在HGF / SF介导的人前列腺癌（DU-145）和Madin-Darby犬肾（MDCK）上皮细胞上对抗ADR的作用。 HGF / SF导致NF-B的P65（RelA）亚基的快速易迁移与抑制亚基IB-抑制次级损失相关的NF-B-。接触HGF / SF导致通过突变体“超级阻遏物”IB-的表达阻断或减弱的NF-B荧光素酶报告器的活化。电泳迁移率移位测定超滤试验显示HGF / SF处理诱导各种NF-B系列（P65，P50，C-Rel和RelB）的瞬时结合，其具有放射性标记的NF-B结合寡核苷酸。通过IB-消除了HGF / SF介导的DU-145和MDCK细胞对ADR的保护（使用MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑鎓溴化物）测定）。超级压缩机。 HGF / SF激活NF-B信令的能力取决于C-AKT PAK1（P21相关激酶-1）信号传导（C-AKT的下游PAK1），并被肿瘤抑制剂PTEN（磷酸酶和张素同源物）抑制）。磷脂酰肌醇-3'-激酶和SRC系列激酶的抑制剂显着抑制了NF-B的HGF / SF介导的活化，而MEK，蛋白激酶C和P70 S6激酶的抑制剂对NF-B活性产生了适度或没有影响。 HGF / SF在NF-B中诱导几种已知的NF-B靶基因的表达（CIAP-1（细胞凋亡-1），CIAP-2和TNF受体相关因子-2）的表达） - 依赖的方式; HGF / SF阻断ADR抑制这些基因的表达。实验性操纵这些基因的表达表明它们（特别是Traf-2和CIAP-2）有助于通过HGF / SF对抗ADR。这些发现表明HGF / SF通过C-AKT PAK1信号传导途径激活NF-B，其也依赖于SRC，并且NF-B有助于对ADR的HGF / SF介导的保护。

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