TRANSCRIPTIONAL REGULATION OF THE HUMAN S100-BETA GENE

S100 beta is a calcium-binding protein produced and secreted by glial cells in the central and peripheral nervous systems. S100 beta promote s neuronal differentiation and survival but may be detrimental to cell s if overexpressed. The selective overproduction of S100 beta has been implicated in the progression of the neuropathological changes in Alz heimer's disease. In addition, at high concentrations, S100 beta stimu lates toxic intracellular pathways in cultured cells. To begin to defi ne the regulation of S100 beta expression, we characterized the human S100 beta promoter and mapped its upstream regulatory elements by usin g a luciferase reporter system. The functional S100 beta promoter was localized to a region -168/+697 containing 168 bp upstream of the tran scription initiation site of the gene. This minimal promoter was activ e in a variety of cell types, including those of glial, neuronal, and non-neural origin. The human S100 beta promoter activity is regulated by both positive and negative regulatory elements located upstream in the 5' flanking DNA regions. The regions -788/-391 and -1012/-788 cont ain strong positive, cell type-specific regulatory elements. Negative regulatory elements were mapped to the more distal -4437/-1012 and -10 12/-788 regions of the gene. The -4437/-1012 negative element suppress ed promoter activity in all cell types examined, except C6 glioma cell s. These data demonstrate that the expression of the human S100 beta g ene is under complex transcriptional regulation that allows for precis e control of the S100 beta level in the nervous system.