AP-1 AND ETS TRANSCRIPTION FACTORS REGULATE THE EXPRESSION OF THE HUMAN SPRR1A KERATINOCYTE TERMINAL DIFFERENTIATION MARKER

The 173-base pair proximal promoter of SPRR1A is necessary and suffici ent for regulated expression in primary keratinocytes induced to diffe rentiate either by increasing extracellular calcium or by 12-O-tetrade canoylphorbol-13-acetate (TPA) treatment. Whereas calcium-induced expr ession depends both on an AP-1 and an Ets binding site in this region, responsiveness to TPA resides mainly (but not exclusively) on the Ets element, indicating that Ets factors are important targets for protei n kinase C signaling during keratinocyte terminal differentiation. Thi s conclusion is further substantiated by the finding that expression o f ESE-1, an Ets transcription factor involved in SPRR regulation, is a lso induced by TPA, with kinetics similar to SPRR1A. The strict AP-1 r equirement in SPRR1A for calcium-induced differentiation is not found for SPRR2A, despite the presence of an identical AP-I consensus bindin g site in this gene. Binding site swapping indicates that both the nuc leotides flanking the TGAGTCA core sequence and the global promoter co ntext are essential in determining the contribution of AP-1 factors in gene expression during keratinocyte terminal differentiation. In the distal SPRR1A promoter region, a complex arrangement of positive and n egative regulatory elements, which are only conditionally needed for p romoter activity, are likely involved in gene-specific fine-tuning of the expression of this member of the SPRR gene family.