BACKGROUND Nickel and nickel-containing compounds (NCC) are known human carcinogens. However, the precise molecular mechanisms of nickel-induced malignant transformation remain unknown. Proposed mechanisms suggest that nickel and NCC may participate in the dual activation/inactivation of enzymatic pathways involved in cell defenses against oxidative damage, where Nuclear factor-erythroid 2 related factor 2 (Nrf2) plays a central role. METHODS For assessing the potential role of proteins involved in the Nrf2-mediated response to nickel and NCC exposure, we designed an interactome network using the STITCH search engine version 5.0 and the STRING software 10.0. The major NCC-protein interactome (NCPI) generated was analyzed using the MCODE plugin, version 1.5.1 for the detection of interaction modules or subnetworks. Main centralities of the NCPI were determined with the CentiScape 2.2 plugin of Cytoscape 3.4.0 and main biological processes associated with each cluster were assessed using the BiNGO plugin of Cytoscape 3.4.0. RESULTS Water-soluble NiSO4 and insoluble Ni3S2 were the most connected to proteins involved in the NCPI network. Nfr2 was detected as one of the most relevant proteins in the network, participating in several multifunctional protein complexes in clusters 1, 2, 3 and 5. Ontological analysis of cluster 3 revealed several processes related to unfolded protein response (UPR) and response to endoplasmic reticulum (ER) stress. CONCLUSIONS Cellular response to NCC exposure was very comparable, particularly concerning oxidative stress response, inflammation, cell cycle/proliferation, and apoptosis. In this cellular response, Nfr2 was highly centralized and participated in several multifunctional protein complexes, including several related to ER-stress. These results add evidence on the possible Ni2+ induced - ER stress mainly associated with insoluble NCC. In this scenario, we also show how protein degradation mediated by ubiquitination seems to play key roles in cellular responses to Ni.

中文翻译：

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镍暴露中的核因子类红细胞2-相关因子2及其与细胞反应的关系：系统生物学分析。

背景技术镍和含镍化合物（NCC）是已知的人类致癌物。但是，镍诱导的恶性转化的确切分子机制仍然未知。拟议的机制表明，镍和NCC可能参与涉及细胞防御氧化损伤的酶促途径的双重激活/失活，其中核因子-类胡萝卜素2相关因子2（Nrf2）起着核心作用。方法为了评估参与Nrf2介导的镍和NCC暴露反应的蛋白质的潜在作用，我们使用STITCH搜索引擎5.0版和STRING软件10.0版设计了一个相互作用组网络。使用MCODE插件1.5.1版对生成的主要NCC-蛋白质相互作用组（NCPI）进行了分析，以检测相互作用模块或子网。使用Cytoscape 3.4.0的CentiScape 2.2插件确定了NCPI的主要中心，并使用Cytoscape 3.4.0的BiNGO插件评估了与每个簇相关的主要生物学过程。结果水溶性NiSO4和不溶性Ni3S2与NCPI网络中涉及的蛋白质联系最紧密。Nfr2被检测为网络中最相关的蛋白质之一，参与了簇1、2、3和5中的几种多功能蛋白质复合物。对簇3的本体分析表明，一些过程涉及未折叠的蛋白反应（UPR）和对内质的反应网状网（ER）压力。结论细胞对NCC暴露的反应非常可比，特别是在氧化应激反应，炎症，细胞周期/增殖和凋亡方面。在这种细胞反应中 Nfr2是高度集中的，并参与了几种多功能蛋白复合物，包括与ER应激有关的几种复合物。这些结果为可能的Ni2 +诱导的-ER胁迫主要与不溶性NCC相关提供了证据。在这种情况下，我们还显示了泛素介导的蛋白质降解在细胞对Ni的反应中似乎起着关键作用。