Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1
Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1
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DOI：
10.1093/emboj/17.10.2846
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发表时间：
1998-05-15
期刊：
影响因子：
11.4
通讯作者：
Schaffner, W
中科院分区：
文献类型：
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作者：
Günes, Ç;Heuchel, R;Schaffner, W
我们之前已经证明重金属响应转录激活因子MTF-1调节基础和重金属诱导的金属硫蛋白表达，为了研究MTF-1的生理功能，我们通过靶向基因破坏产生零突变小鼠。缺乏MTF-1的胚胎大约在妊娠第14天在子宫内死亡。它们表现为肝细胞发育受损，在后期表现为肝腐烂和全身性水肿。MTF-1（-/-）胚胎无法转录金属硫蛋白I和II基因，并且编码谷胱甘肽生物合成关键酶- γ -谷氨酰半胱氨酸合成酶重链亚基的基因转录减少。金属硫蛋白和谷胱甘肽参与重金属稳态和解毒过程，如清除活性氧中间体。因此，缺乏MTF-1的原代小鼠胚胎成纤维细胞对镉或过氧化氢的细胞毒性作用的敏感性增加，因此，MTF-1可能有助于控制金属稳态和细胞氧化还原状态，特别是在肝脏发育过程中。我们还注意到，MTF-1零突变表型与其他两种细胞应激反应调节因子，即c-Jun和NF-kappa B （p65/RelA）有一些相似之处。
We have shown previously that the heavy metal-responsive transcriptional activator MTF-1 regulates the basal and heavy metal-induced expression of metallothioneins, To investigate the physiological function of MTF-1, we generated null mutant mice by targeted gene disruption. Embryos lacking MTF-1 die in utero at approximately day 14 of gestation. They show impaired development of hepatocytes and, at later stages, liver decay and generalized edema. MTF-1(-/-) embryos fail to transcribe metallothionein I and II genes, and also show diminished transcripts of the gene which encodes the heavy-chain subunit of the gamma-glutamylcysteine synthetase, a key enzyme for glutathione biosynthesis. Metallothionein and glutathione are involved in heavy metal homeostasis and detoxification processes, such as scavenging reactive oxygen intermediates. Accordingly, primary mouse embryo fibroblasts lacking MTF-1 show increased susceptibility to the cytotoxic effects of cadmium or hydrogen peroxide, Thus, MTF-1 may help to control metal homeostasis and probably cellular redox state, especially during liver development. We also note that the MTF-1 null mutant phenotype hears some similarity to those of two other regulators of cellular stress response, namely c-Jun and NF-kappa B (p65/RelA).