95% of all human cancers are of epithelial origin. Keratin 18 is persistently expressed in the majority of these; its expression is reliable enough to be used as a marker for distinguishing tumors of epithelial origin. Furthermore, K18 has recently been identified as a target of the ras signal transduction pathway, which may suggest a function for K18 in tumor biology. Metastatic behavior is a major contributor to the lethality of cancer; other genes shown to be responsive to the ras signal transduction pathway appear to support metastasis. Therefore, an understanding of the regulation of human keratin 18 expression could eventually aid in the development of cancer treatments. In addition, K18 provides a means of evaluating transcription mechanisms that are associated with invasive behavior. The primary goal of this research proposal is to characterize the tissue-specific chromatin state of the human keratin 18 gene, to identify the sequences necessary for the establishment of an appropriate chromatin state during development, and to begin to investigate the mechanism of their action. It is becoming increasingly clear that transcriptional control cannot be fully understood outside of the chromatin context. For this reason the unique nature of the keratin l 8 gene: Its small gene domain directs tissue-specific, position independent and copy number dependent expression in transgenic mice, makes it an ideal model with which to study the role of chromatin structure in the developmental control of gene regulation. The information gained by these studies should be relevant to many different genes and therefore will contribute to a greater understanding of gene expression in general. Furthermore, understanding the components of a gene domain which impart tissue-specific and position independent expression may be essential for the success of some gene therapy techniques.
