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Journal article

Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1.

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  • 1998-06-10
Published in:
  • The EMBO journal. - 1998
Animals
Cadmium
Cells, Cultured
DNA-Binding Proteins
Dipeptides
Edema
Embryonic and Fetal Development
Female
Fetal Diseases
Fibroblasts
Gene Expression Regulation
Gene Targeting
Glutathione Synthase
Hydrogen Peroxide
Liver
Liver Diseases
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Transcription Factors
English 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 bears some similarity to those of two other regulators of cellular stress response, namely c-Jun and NF-kappaB (p65/RelA).
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/220962
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