Nrf1 is critical for redox balance and survival of liver cells during development
Nrf1 is critical for redox balance and survival of liver cells during development
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DOI：
10.1128/mcb.23.13.4673-4686.2003
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发表时间：
2003-07-01
影响因子：
5.3
通讯作者：
Chan, JY
中科院分区：
文献类型：
--
作者：
Chen, LY;Kwong, M;Chan, JY
Nrf1转录因子属于碱性亮氨酸拉链蛋白的CnC亚家族。Nrf1基因敲除在小鼠胚胎中是致命的，但对于在发育过程中绝对需要Nrf1功能的细胞类型尚不清楚。我们通过嵌合体分析表明，Nrf1是肝细胞系所必需的。缺乏Nrf1的小鼠胚胎干细胞发育正常，并在正常表达Nrf1的成体嵌合体中贡献了大部分组织。NRF1缺陷的细胞对胎儿肝细胞有贡献，但对成人肝细胞没有贡献。Nrf1功能缺失导致妊娠晚期嵌合体胎儿肝细胞凋亡。来自突变胚胎的胎肝表现出氧化应激增加和抗氧化基因表达受损，而原代培养的nrf1(-/-)胎肝细胞对叔丁基氢过氧化氢诱导的细胞死亡敏感，这表明抗氧化防御受损可能是嵌合小鼠肝脏细胞凋亡的原因。此外，Nrf1基因缺失的细胞对肿瘤坏死因子(TNF)的细胞毒作用敏感。我们的结果提供了体内证据，证明Nrf1在肝细胞发育过程中的生存中起着重要作用。我们的结果还表明，Nrf1可能通过维持氧化还原平衡和保护胚胎肝细胞在发育过程中免受肿瘤坏死因子介导的凋亡而促进细胞存活。
The Nrf1 transcription factor belongs to the CNC subfamily of basic leucine zipper proteins. Knockout of Nrf1 is lethal in mouse embryos, but nothing is known about the cell types that absolutely require its function during development. We show by chimera analysis that Nrf1 is essential for the hepatocyte lineage. Mouse embryonic stem cells lacking Nrf1 developed normally and contributed to most tissues in adult chimeras where Nrf1 is normally expressed. Nrf1-deficient cells contributed to fetal, but not adult, liver cells. Loss of Nrf1 function resulted in liver cell apoptosis in late-gestation chimeric fetuses. Fetal livers from mutant embryos exhibited increased oxidative stress and impaired expression of antioxidant genes, and primary cultures of nrf1(-/-) fetal hepatocytes were sensitive to tert-butyl hydroperoxide-induced cell death, suggesting that impaired antioxidant defense may be responsible for the apoptosis observed in the livers of chimeric mice. In addition, cells deficient in Nrf1 were sensitized to the cytotoxic effects of tumor necrosis factor (TNF). Our results provide in vivo evidence demonstrating an essential role of Nrf1 in the survival of hepatocytes during development. Our results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development.