Regulation of matrix metalloproteinase gene expression

Abstract

The metalloproteinases degrade extracellular matrix (ECM) components and activate growth factors, thereby contributing to physiological events (tissue remodeling in pregnancy, wound healing, angiogenesis) and pathological conditions (cancer, arthritis, periodontitis). The intent of this review is to bring together various studies on transcriptional and post-transcriptional control of metalloproteinase expression. Certainly, much information is known as to the cis-elements and corresponding trans-activators regulating expression of these genes. We discuss the fact that a number of the metalloproteinase promoters share common structural features and, therefore, not surprisingly are co-regulated in their expression to some extent. More recently, much effort has been devoted to understanding the role of chromatin in regulating gene expression. While this area has been understudied with respect to matrix metalloproteinase (MMP) regulation, the literature indicates a convincing role for both histone modifications and chromatin-remodeling motors in controlling expression of multiple metalloproteinases. In addition to transcriptional control, mRNA stability and protein translation also contribute to the metalloproteinase product amount. We discuss such studies and how various biological cues, including TGF-b, regulate the levels of certain collagenases either solely through mRNA stabilization or by jointly targeting transcriptional and post-transcriptional mechanisms. We also discuss the current deficits in our knowledge, concerning tissue-specific expression and why despite elevated amounts/activity of trans-activators targeting MMP promoters in tumor cells, nevertheless, MMP expression is largely restricted to the stromal compartment. Finally, we argue for potential technologies to regulate MMP expression of utility in pathological conditions where these enzymes are aberrantly expressed.J cis-Elements and trans-Activators Regulating MMP Gene ExpressionAmple evidence indicates that MMP gene expression is, to a large extent, regulated at the transcriptional level. Indeed, the MMP promoters harbor several cis-elements allowing for the regulation of MMP gene expression by a diverse set of trans-activators including AP-1, PEA3, Sp-1, b-catenin/Tcf-4, and NF-kB (Fig. 1). Several of the MMP promoters are strikingly similar ( Fig. 1) and, in fact, share several cis-elements (Fig. 1), consistent with observations that some MMPs are co-regulated in their expression. In contrast, and somewhat surprisingly, the composition of the promoters of functionally related MMPs such as MMP-2/MMP-9 (gelatinase) or MMP-1/MMP-8 (collagenase) are distinct. Based on the composition of cis-elements, the MMP promoters can be roughly grouped into three categories (Fig. 1). The first group, including the majority of the MMP promoters, contains a TATA box at approximately À30 bp (relative to the transcription start site) and an AP-1-binding site at approximately À70 bp. Most of these promoters also contain an upstream PEA3-binding site that is ofte...

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