WOUND REEPITHELIALIZATION ACTIVATES A GROWTH FACTOR-RESPONSIVE ENHANCER IN MIGRATING KERATINOCYTES

Wound reepithelialization and keratinocyte migration require strictly ordered gene expression, which is assumed to be initiated by locally r eleased mitogens and exposure of the cells to different matrix compone nts. The mechanisms triggering gene expression specifically during ree pithelialization are poorly understood. The far upstream AP-1-driven, FGF-inducible response element (FiRE) of the syndecan-1 gene was activ ated during cutaneous wound healing in transgenic mice, FiRE was induc ed selectively in migrating but not in proliferating keratinocytes at the wound edge, The activation was initiated at the start of the cell migration, was persistent throughout the merging and stratification ph ases, and was terminated after completion of reepithelialization. Alth ough FiRE has been found within the gene of syndecan-1, the proximal p romoter of syndecan-1 was not required for activation of FiRE in the m igrating keratinocytes. The wounding induced activation was inhibited by blocking cell surface growth factor receptors with suramin, However , the activation of FiRE in resting skin required simultaneous growth factor- and stress-induced signals, but could also be elicited by the phosphatase inhibitor, okadaic acid, The activation by both wounding a nd chemical stimuli was blocked by inhibiting extracellular regulated kinase and p38 MAP kinases, suggesting the involvement of at least two parallel signal transduction pathways in wounding induced gene activa tion. As FiRE shows specificity for migrating keratinocytes only, it c an be a useful tool for future wound healing studies and for targeting genes to injured tissues.