This project proposed to morphologically and biochemically define the mechanism of action of vitamin A and its derivatives (retinoids) in altering epidermal differentiation in normal skin and in benign and malignant lesions of skin. Topical alltrans retinoic acid, but not systemic 13-cis-retinoic acid, increased gap junction density and decreased desmosome density in treated basal cell carcinomas. This indicates that topical and systemic retinoids may exert their antineoplastic activity by different cellular mechanisms. A specific cytosol retinol binding protein (CRBP) has been identified in normal human skin, newborn mouse skin and human skin from patients with Darier's disease, psoriasis and basal cell carcinomas. A specific cytosol retinoic acid binding protein (CRABP) has also been identified in newborn mouse and normal human adult skin and newborn foreskin. The qualitative and quantitative distribution between the epidermis and dermis of both CRBP and CRABP has been determined in adult human lower limb skin. Using molecular hybridization probes specific for transcripts of individual keratin genes, keratin gene expression in skin cancer and cutaneous disorders of keratinization indicate the following. In contrast to normal epidermis where the expression of proliferation-associated keratin genes is suppressed after cells migrate from the basement membrane, hyperproliferative disorders of the epidermis exhibit inappropriate expression of proliferation- associated keratin genes in the more superficial layers of the epidermis. In addition, skin cancers fail to express differentiation-associated keratins, indicative of their undifferentiated state.
