Secalonic acid D alters the nature of and inhibits the binding of the transcription factors to the phorbol 12-O-tetradecanoate-13 acetate-response element in the developing murine secondary palate
G. Balasubramanian et al., Secalonic acid D alters the nature of and inhibits the binding of the transcription factors to the phorbol 12-O-tetradecanoate-13 acetate-response element in the developing murine secondary palate, TOX APPL PH, 169(2), 2000, pp. 142-150
Secalonic acid D (SAD), a mycotoxin produced by Penicillium oxalicum in cor
n, induces cleft palate (CP) in the offspring of exposed darns. Results of
recent studies suggest that protein kinase C (PKC) inhibition by SAD may be
relevant to its CP-induction. Downstream effects of PKC are determined by
the nature of transcription factors (TF) that form the activator protein-1
(AP-1) and the binding of AP-1 land other TF) to the phorbol 12-O-tetradeca
noate-13 acetate-response element (TRE) to form AP-1-TRE complex, neither o
f which have been studied in the palate. The aims of the present study were
to identify the components of the murine palatal AP-1-TRE complex during d
evelopment and to uncover the effects of SAD on this complex. Western blots
and gel mobility shift assays of control palatal nuclear extracts revealed
that, although all relevant TF are present in the palate throughout develo
pment, only cyclic-AMP response element (CRE) binding protein (CREB) and CR
E-modulator protein-1 (CREM-1) and activating transcription factor-1 bound
to TRE on Gestation Day (GD) 12. The pattern shifted to c-Jun and c-Fos (kn
own AP-1 components) on GD 13 and 14. In SAD-treated offspring, however, CR
EM-1 alone; c-Jun, c-Fos, and CREB; and c-Jun and c-Fos bound to TRE on GD
12, 13, and 14, respectively. Binding of TF to TRE was inhibited by SAD on
both GD 12 and 13. These results suggest that a dynamic shift in the bindin
g of TF to TRE from PKA- to PKC-responsive TF occurs during palate developm
ent and that teratogens such as SAD can alter both the nature and extent of
TF binding to TRE. (C) 2000 Academic Press.