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Vol. 280, Issue 2, 1085-1093, 1997
and
Department of Pharmacology and Therapeutics, McGill University,
Montréal, Québec, Canada
The transcription factor activator protein-1 (AP-1), composed of the
Fos and Jun families of proto-oncogenes, is induced in response to
extracellular signals as part of an immediate-early gene response. We
hypothesize that teratogens such as oxidative stress induce AP-1
activity in the rat conceptus and that this AP-1 response may either
trigger abnormal development or protect the embryo against insult. To
test this hypothesis, the AP-1 response was assessed in whole embryos
in culture. There was a significant elevation in the oxidized to
reduced glutathione ratio in the embryo and yolk sac within 0.25 hr of
the initiation of culture, peaking at 0.5 hr; this is indicative of
heightened oxidative stress. At 0.5 hr protein oxidation was also
enhanced, as demonstrated by increased protein reactivity with
2,4-dinitrophenylhydrazine. In the conceptus, the steady-state
concentrations of c-fos, c-jun, junB
and junD mRNAs were induced, peaking at 0.5 hr and returning to base line by 1 to 2 hr in the embryo and by 1 to 6 hr in the yolk
sac. Electrophoretic mobility shift assays showed enhanced AP-1
DNA-binding activity in both the embryo (elevated by 0.5 hr and
persisting for 1 hr) and the yolk sac (persisting for 3 hr). Thus,
there are tissue-specific differences in the duration of the AP-1
response in the conceptus. Addition of the antioxidants catalase and
superoxide dismutase, but not vitamin E, prevented the rise in the
oxidized to reduced glutathione ratio and also inhibited the induction
of AP-1 mRNAs and DNA-binding activity. The AP-1 response to oxidative
stress may determine how the conceptus responds to insult.
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