SYNERGISTIC TRANSCRIPTIONAL ACTIVATION OF THE TISSUE INHIBITOR OF METALLOPROTEINASES-1 PROMOTER VIA FUNCTIONAL INTERACTION OF AP-1 AND ETS-1 TRANSCRIPTION FACTORS

The tissue inhibitor of metalloproteinases-1 (TIMP-1) is an inhibitor of the extracellular matrix-degrading metalloproteinases, We character ized response elements that control TIMP-1 gene expression. One contai ns a binding site that selectively binds c-Fos and c-Jun in, vitro and confers a response to multiple AP-1 family members in vivo. Adjacent to this is a binding site for Ets domain proteins. Although c-Ets-1 al one did not activate transcription from this element, it enhanced tran scription synergistically with AP-1 either in the context of the natur al promoter or when the sequence was linked upstream of a heterologous promoter, Furthermore, a complex of c-Jun and c-Fos interacted with c -Ets-1 in vitro. These results suggest that AP-1 tethers c-Ets-1 to th e TIMP-1 promoter via protein-protein interaction to achieve Ets depen dent transcriptional regulation. Collectively, our results indicate th at TIMP-1 expression is controlled by several DNA response elements th at respond to variations in the level and activity of AP-1 and Ets tra nscriptional regulatory proteins.