The AP-1 site and MMP gene regulation: what is all the fuss about?

Matrix metalloproteinase (MMP) gene expression occurs under tightly regulated mechanisms that lead to cell and tissue-specific expression of the individual genes. Despite this differential expression, there exists a high degree of similarity among the cis-acting elements in the MMP promoters. The Activator Protein-1 (AP-1) site at approximately -70 bp upstream of the transcriptional start site has long been thought to play a dominant role in the transcriptional activation of the MMP promoters, particularly in response to stimulation with phorbol myristate acetate (PMA). However, more recent data indicate that basal transcription, as well as transactivation by PMA, cytokines, and growth factors requires the specific interaction of AP-1 with other cis-acting elements. Particularly important are PEA3 sites, located either adjacent to this AP-1 site or more distally. On the otherhand, the AP-1 site plays a dominant role in repression of MMPs by transforming growth factor beta (TGF-beta), retinoids and glucocorticoids, although some AP-1 independent mechanisms may also contribute. While the AP-1 site is involved in tissue-specific expression of MMPs, the presence of one or more AP-2 elements appears critical. Thus, the AP-1 site, alone, does not regulate transcription of MMPs. Rather, there is an essential interaction with other cis-acting sequences in the promoters and with certain transcription factors that bind to these sequences. Together, these complex interactions control the transcription of the MMPs in response to particular inducers and repressors.