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FBX06 attenuates cadmium toxicity in HEK293 cells by inhibiting ER stress and JNK activation

机译:FBX06通过抑制ER应激和JNK激活来减轻HEK293细胞中的镉毒性

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摘要

Cadmium-induced cell death is associated with endoplasmic reticulum (ER) stress. We previously found that inhibition of FBXO6 expression, which is a ubiquitin ligase involved in ER-associated protein degradation (ERAD), induces high sensitivity to cadmium in HEK293 cells. However, the precise role of FBXO6 in ER stress remains unexplored. In this study, we investigated the role of FBXO6 in cadmium-induced ER stress in HEK293 cells. Our results showed that the cadmium-induced increase in expression of the ER stress marker proteins, BiP and CHOP, was further enhanced by inhibiting FBXO6 expression. Cadmium-induced c-Jun phosphorylation was also markedly increased by inhibition of FBXO6 expression. However, this c-Jun phosphorylation was almost entirely abolished by inhibition of c-Jun N-terminal kinase 1 (JNK1) expression. The level of high cadmium sensitivity induced by inhibition of FBXO6 expression was markedly lower in the JNK1-ablated cells than in the control cells. In addition, cadmium elevated the cellular level of ERAD substrate proteins, and this elevation was further enhanced by inhibiting FBXO6 expression. These results suggest that FBXO6 might inhibit cadmium-induced ER stress by functioning as a ubiquitin ligase in the ERAD system, thereby attenuating the cell death induced by subsequent JNK1 activation.
机译:镉诱导的细胞死亡与内质网(ER)应激有关。我们先前发现抑制FBXO6表达是一种参与ER相关蛋白降解(ERAD)的泛素连接酶,可诱导HEK293细胞对镉的高敏感性。但是,FBXO6在内质网应激中的确切作用尚待探索。在这项研究中,我们调查了FBXO6在HEK293细胞中镉诱导的ER应激中的作用。我们的结果表明,通过抑制FBXO6的表达,镉诱导的ER应激标记蛋白BiP和CHOP的表达增加。镉诱导的c-Jun磷酸化也通过抑制FBXO6表达而明显增加。但是,这种c-Jun磷酸化几乎完全被抑制c-Jun N端激酶1(JNK1)的表达所消除。通过抑制FBXO6表达诱导的高镉敏感性水平在JNK1消融细胞中明显低于对照细胞。另外,镉升高了ERAD底物蛋白的细胞水平,并且这种升高通过抑制FBXO6表达而进一步增强。这些结果表明,FBXO6可能通过在ERAD系统中起泛素连接酶的作用来抑制镉诱导的内质网应激,从而减轻随后的JNK1激活诱导的细胞死亡。

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