Transcriptional regulation of the human TIMP-1 gene: mapping control elements in intron-1

Abstract

The matrix metalloproteinases (MMPs) are a family of enzymes involved in the turnover and degradation of extracellular matrix. The active form of all MMPs are inhibited by a family of specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). An imbalance of MMP and TIMP activity is associated with aberrant matrix turnover in a number of pathologies, therefore an understanding of TIMP-1 gene regulation is an important step in the possible therapeutic modulation of TIMP-1 levels. In our initial studies, a 2.9kb clone of the human TIMP-1 gene was sequenced and determined to contain 1.7kb upstream of exon-1, exon-1, intron-1, exon-2 and the start of intron-2 (Clark et al. 1997). We demonstrated the importance of an AP-1 and PEA3 site located just upstream of exon-1 in basal transcription (Clark et al. 1997). However, studies with the murine TIMP-1 gene have suggested that intron 1 also contains important regulatory elements (Flenniken & Williams 1990); here, we investigate this possibility in our system.