The normal growth and differentiation of epithelial cells is essential to maintaining cutaneous, respiratory, gastrointestinal, and genitourinary environmental barriers. The major types of human cancers develop from cells which retain significant proliferative capacity in adult organs or tissues. Epithelial cells are particularly important in this regard, since the majority of human cancers are carcinomas derived from stratified epithelial tissues (epidermoid carcinomas) or glandular epithelium (adenocarcinomas). In addition to their key role in the pathogenesis of human cancers, abnormal growth of epithelial cells defines a wide variety of pathological hyperplasias and premalignant dysplasias. Human keratinocytes in culture and pathological epidermal tissue can be used as a general model to study regulation of normal and pathological growth of epithelial cells. The overall goals of proposed research are to determine biochemical pathways involved in early events of mitogenic signaling in human keratinocytes and to determine whether aberrant regulation of these pathways is involved in the pathogenesis of epidermal hyperplasias and neoplasias. Preliminary work has concentrated on the role of receptor-type and non-receptor-type tyrosine kinases in regulation of keratinocyte proliferation and differentiation. In particular, human keratinocytes express high levels of the proto-oncogene product of the c-yes gene (termed p62c-yes), a non-receptor-type tyrosine kinase. Preliminary experiments establish that expression of p62c-yes is altered in human carcinomas derived from keratinocytes and suggest that p62c-yes might regulate cell growth through physical association with the EGF receptor. Experiments are proposed to study functional linkages between expression of membrane tyrosine kinases (receptor- and non-receptor-types), regulation of keratinocyte proliferation and differentiation, and the pathogenesis of epidermal hyperplasias and neoplasias. In particular, the potential of p62c-yes to function as a tumor (proliferative) suppressor protein/positive inducer of differentiation will be investigated in normal and neoplastic keratinocytes by transfection of c-yes expression constructs in which transcription of c-yes is regulated by exogenous promotors.
