TRANSCRIPTIONAL REGULATION OF THE DIFFERENTIATION-LINKED HUMAN K4 PROMOTER IS DEPENDENT UPON ESOPHAGEAL-SPECIFIC NUCLEAR FACTORS

The stratified squamous epithelium comprises actively proliferating ba sal cells that undergo a program of differentiation accompanied by mor phological, biochemical, and genetic changes. The transcriptional regu latory signals and the genes that orchestrate this snitch from prolife ration to differentiation can he studied through the keratin gene fami ly. Givers the localization of keratin 4 (K4) to the early differentia ted suprabasal compartment sand leaving previously demonstrated that t argeted disruption of this gene in murine embryonic stem cells results in impairment of the normal differentiation program in esophageal and corneal epithelial cells, we studied the transcriptional regulation o f the human K4 promoter. A panel of K4 promoter deletions were found i n transient transfection assays to be predominantly active in esophage al and corneal cell lines. A critical cis-regulatory element resides b etween -163 and -140 bp and contains an inverted CACACCT motif. A site -directed mutated version of this motif within the K4 promoter renders it inactive, whereas the wild-type version is active in a heterologou s promoter system. It specifically binds esophageal-specific zinc-depe ndent transcriptional factors. Our studies demonstrate that regulation of the human K4 promoter is in part mediated through tissue-specific transcriptional factors.