Identification of a serum- and phorbol ester-responsive element in the murine tissue inhibitor of metalloproteinase gene.

Tissue inhibitor of metalloproteinase (TIMP) is one of a family of metalloproteinase inhibitors and a major interstitial inhibitor of collagenase. Transcription of the TIMP gene is induced by such diverse agents as viruses, phorbol esters, serum, and growth factors. We have previously assigned the regulatory elements responsible for induction of transcription in response to viruses to the first intron of the murine TIMP gene. Here we have identified a promoter and an enhancer element responsive to serum and the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. Based on a comparative sequence analysis of the murine and human genes, the enhancer element is part of a 38-base pair conserved sequence. Gel mobility shift assays indicate that this enhancer is a phorbol ester-responsive-like element that likely binds one of a family of AP-1 proteins. Interestingly, the region containing the phorbol ester-responsive-like element is also sufficient to direct a response to transforming growth factor beta 1 in the presence of serum.