A regulatory element of the human keratin 18 gene with AP-1-dependent promoter activity

The human keratin 18 (K18) gene is expressed in a restricted but diverse subset of differentiated epithelial tissues and carcinomas. The 10-kilobase pair K18 gene contains all of the genetic information necessary for tissue-specific, copy number-dependent and integration site-independent expression in transgenic mice. We identified a 100-base pair regulatory element that activates the K18 proximal promoter in the presence of the previously identified first intron enhancer. Deletion of the element greatly diminished K18 expression. This regulatory element also has cryptic, AP-1-dependent promoter activity in the absence of the normal promoter, which results in 10-40-fold higher levels of K18 RNA expression in transgenic mice. The high activity of this cryptic promoter is dependent upon the first intron enhancer. These experiments define interactive regulatory regions of the K18 gene that modulate expression in diverse epithelial cell types and identify an unusual regulatory element with promoter activity that may be useful for high level heterologous gene expression in transgenic animals.