Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1.
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).
Günes
C
C
Institut für Molekularbiologie, Abteilung II der Universität Zürich, Zürich, Switzerland.
Heuchel
R
R
Georgiev
O
O
Müller
K H
KH
Lichtlen
P
P
Blüthmann
H
H
Marino
S
S
Aguzzi
A
A
Schaffner
W
W
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004151:Dipeptides; D004487:Edema / Q000209:etiology*; D005314:Embryonic and Fetal Development; D005260:Female; D005315:Fetal Diseases; D005347:Fibroblasts; D005786:Gene Expression Regulation; D018390:Gene Targeting; D005981:Glutathione Synthase / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008099:Liver / Q000196:embryology* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000097809:Transcription Factor MTF-1
D002104:Cadmium; D004268:DNA-Binding Proteins; D004151:Dipeptides; D005981:Glutathione Synthase; D006861:Hydrogen Peroxide; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C017341:gamma-glutamylcysteine