THE AP-1 SITE AND MMP GENE-REGULATION - WHAT IS ALL THE FUSS ABOUT

Matrix metalloproteinase (MMP) gene expression occurs under tightly re gulated mechanisms that lead to cell and tissue-specific expression of the individual genes. Despite this differential expression, there exi sts a high degree of similarity among the cis-acting elements in the M MP promoters. The Activator Protein-1 (AP-1) site at approximately -70 bp upstream of the transcriptional start site has long been thought t o play a dominant role in the transcriptional activation of the MMP pr omoters, particularly in response to stimulation with phorbol myristat e acetate (PMA). However, more recent data indicate that basal transcr iption, as well as transactivation by PMA, cytokines, and growth facto rs requires the specific interaction of AP-1 with other cis-acting ele ments. Particularly important are PEA3 sites, located either adjacent to this AP-1 site or more distally. On the otherhand, the AP-1 site pl ays a dominant role in repression of MMPs by transforming growth facto r beta (TGF-beta), retinoids and glucocorticoids, although some AP-1 i ndependent mechanisms may also contribute. While the AP-1 site is invo lved in tissue-specific expression of MMPs, the presence of one or mor e AP-2 elements appears critical. Thus, the AP-1 site, alone, does not regulate transcription of MMPs. Rather, there is an essential interac tion with other cis-acting sequences in the promoters and with certain transcription factors that bind to these sequences. Together, these c omplex interactions control the transcription of the MMPs in response to particular inducers and repressors.