The human tissue inhibitor of metalloproteinases (TIMP)-1 gene contains repressive elements within the promoter and intron 1

Expression of the TIMP-1 (tissue inhibitor of metalloproteinases-l) gene is tightly controlled during embryonic development and in the adult animal, P revious studies have focused on elements within the gene promoter which act ivate transcription of the gene. Here, we identify two regions of the gene which repress transcription: An element upstream of the basal gene promoter at -1718/-1458, represses expression of a reporter gene by approximately 5 0%; addition of the first intron to any promoter-reporter construct also st rongly represses gene expression. The TIMP-1 gene has a short first exon wh ich is transcribed but not translated, with the translation start site loca ted in exon 2, Deletion analysis through intron 1 reveals a number of poten tial regions which might mediate its effect. Protein binding studies and mu tational analyses reveal that a repressive element at +684/+748 binds Sp1, Sp3, and an unidentified Ets-related factor to suppress transcription.