TRANSCRIPTIONAL CONTROL IN KERATINOCYTES AND FIBROBLASTS USING SYNTHETIC LIGANDS

The skin is an attractive tissue for regulated target gene expression by virtue of its accessibility to topical regulating stimuli. We have used synthetic ligand-driven intracellular oligomerization to accompli sh specific target gene regulation in human skin keratinocytes and fib roblasts. GALA DNA binding domains and VP16 transactivation domains, e ach linked to the FK506 binding protein, were expressed in normal huma n skin keratinocytes and fibroblasts. These hybrid proteins underwent heterodimerization via the novel intracellular dimerizing agent FK1012 to generate a heterodimeric activator of target gene expression in vi tro. Dimeric FK1012, but not monomeric FK506M induced target gene expr ession in a dose-dependent fashion. FK1012 exerted no detectable nonsp ecific effects on expression of cutaneous genes and did not alter cell ular proliferation kinetics. Controlled oligomerization of hybrid tran scription activators offers a potential approach to target gene regula tion in cells of normal human skin.