CODOMINANT REGULATION OF KERATIN GENE-EXPRESSION BY CELL-SURFACE RECEPTORS AND NUCLEAR RECEPTORS

Epidermal keratinocytes are subject to a large variety of signals that modulate their differentiation in health and their activation in dise ase. Hormones and vitamins, which act via nuclear receptors, affect th e differentiation process, whereas growth factors and cytokines, which act via cell surface receptors, affect keratinocyte activation and re lated events. Using expression of keratin genes as markers for keratin ocyte phenotype, we examined the interaction between the nuclear recep tor and cell surface receptor pathways. We expected to find dominance of one of the pathways. Surprisingly, we found that the two pathways a re co-dominant. Specifically, while EGF induces expression of K6 and K 16 keratin genes, retinoic acid suppresses their expression, and when both mediators are present simultaneously, the level of expression is intermediate, a product of both signals. Similar codominant effects we re found on other keratin genes using interferon gamma, TGF beta, and thyroid hormone signaling molecules. These codominant effects are spec ific only for genes that are regulated by both pathways. Our results s uggest that a judicious combination of hormones, vitamins, growth fact ors, and cytokines may be used to target specific expression of approp riate genes in the treatment of human epidermal diseases. (C) 1996 Aca demic Press, Inc.