As with both Ishikawa cell lines, the DDT, DDD, and DDE metabolites in conjunction with PMA all stimulated AP-1 significantly versus control, whereas p,p'-DDA could not induce an effect (Figure 4).
Here we have shown that DDT can directly affect the activity of AP-1, an important cell regulatory factor.
To determine whether DDT and its metabolites induced AP-1 activation through an ER-mediated mechanism, we created human endometrial adenocarcinoma Ishikawa stable cell lines containing an AP-1-responsive promoter linked to a luciferase reporter gene.
Because our estrogen-unresponsive cells give a stronger AP-1 activation, it is possible that the AP-1 signaling mechanisms have been up-regulated to compensate for the loss of responsiveness to estrogen.
Recently, compounds of the DDT family have been reported to affect a number of AP-1 regulated genes in vivo.
AP-1 activation has become a marker for a number of effects elicited initially at the plasma membrane.
Activation of AP-1 and NF[kappa]B at 3 and 18 hr is required for transformation in the JB6 model (13,15).
Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion.
Expression of dominant negative Jun inhibits elevated AP-1 and NF-kappaB transactivation and suppresses anchorage independent growth of HPV immortalized human keratinocytes.
Induced expression of dominant-negative c-jun downregulates NFkappaB and AP-1 target genes and suppresses tumor phenotype in human keratinocytes.
Expression of dominant negative Erk2 inhibits AP-1 transactivation and neoplastic transformation.
Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells.