MECHANISMS IDENTIFIED IN THE TRANSCRIPTIONAL CONTROL OF EPITHELIAL GENE-EXPRESSION

Epithelium specific gene expression is fundamental in both embryogenes is and the maintenance of adult tissues, and impairment of epithelial characteristics contributes to diseases such as cancer. We have here a nalyzed the 5'-region of the epithelial (E-) cadherin gene in order to understand mechanisms of epithelium-specific transcription and loss o f expression during epithelial mesenchymal transitions. The regulatory region of the mouse epithelial cadherin gene is composed of a promote r (from position -94 to the transcription start site) and a 150-base p air enhancer located in the first intron. The 5'-promoter consists of positive regulatory elements (a CCAAT-box and two AP-2 binding sites i n a GC-rich region) and the palindromic element E-Pal that activates a nd represses transcription in epithelial and mesenchymal cells, respec tively. The enhancer of the first intron stimulates the activity of he terologous promoters exclusively in epithelial cells. This epithelium- specific enhancer consists of three elements (E I to E III; E II and E III bind AP-2) that are necessary and sufficient for activity, We thu s propose two regulatory mech anisms by which epithelial specificity o f epithelial cadherin expression is determined: suppression of promote r activity in mesenchymal cells by E-Pal and enhancement of activity i n epithelial cells by both E-Pal and the epithelium specific enhancer.