Interplay between proximal and distal promoter elements is required for squamous differentiation marker induction in the bronchial epithelium: role for XXXX , @entity3419 , and AP-1 proteins.

@entity56787 @entity36612 @entity18437 @entity4515 @entity1359 @entity1178 @entity3419 @entity864 @entity5742
Overexpression of @entity56787 in bronchial epithelial cells is a marker for early metaplastic changes induced by various toxicants/carcinogens. Previously, we have shown that the transcriptional stimulation of @entity56787 expression by @entity1359 ( @entity4515 ) is mainly mediated by a -150/-94 bp enhancer harboring two critical @entity864 -responsive elements (TREs) and by @entity1178 . @entity5742 dimers. Here, we show that a region between -54 and -39 bp containing an ETS-binding site (EBS) and a GC box is essential for both basal and @entity4515 -inducible @entity56787 transcription. In vivo footprinting demonstrated binding of transcription factors to these elements. However, unlike enhancer TREs, exposure of cells to @entity4515 did not significantly alter the footprinting pattern at these elements. Mutations that crippled both the EBS and GC box suppressed both basal and @entity4515 -inducible @entity56787 transcription. Consistent with this, overexpression of EBS-binding proteins @entity18437 and @entity36612 significantly stimulated @entity56787 promoter activity. Furthermore, preceding @entity56787 transcription, @entity4515 up-regulated mRNA expression of ETS family members such as @entity18437 and @entity36612 . Although @entity18437 synergistically activated @entity1178 - and @entity4515 -enhanced @entity56787 transcription, coexpression of @entity3419 and @entity18437 showed no synergistic or additive effect on promoter activity, indicating an obligatory role for AP-1 proteins in such regulation. In support of this notion, deletion or mutation of two functional TREs inhibited @entity18437 - and @entity3419 -enhanced promoter activation. Thus, the interaction between @entity18437 and @entity3419 , and AP-1 proteins that bind to the proximal and distal promoter regions, respectively, play a critical role in the induction of squamous differentiation marker expression in bronchial epithelial cells.
