Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes

Stimulation of the 92-Kd Type Iv Collagenase Promoter and Enzyme Expression in Human Melanoma Cells

The 92-kD type IV collagenase is a member of the metalloproteinase family which degrades type IV collagen, a major component of basement membrane and is involved in tumor invasion and metastasis. The promoter and adjacent regulatory sequences of the 92-kD type IV collagenase have been identified previously and three cis-acting elements homologous to the binding sites for AP-1, NF-KB and SP-1 proteins contributed to induction of the promoter activity by 12-O-tetradecanoylphorbol 13-acetate (TPA) and tumor necrosis factor (TNF-alpha) in HT1080 cells. To date, no direct correlation between promoter activity and expression of the 92-kD type IV collagenase has been reported in normal or cancer cells. In this study, the effects of the transcriptional stimulation of the 92-kD type IV collagenase gene on the expression of the enzyme in human A2058 melanoma cells was analyzed by zymography experiments. Quantitative immunoblots using a monoclonal antibody that recognized specifically and exclusively the 92-kD type IV collagenase, confirmed that the 92-kD gelatinase was 92-kD type IV collagenase. Stimulation of the promoter activity resulted in increased gelatinase activity in the culture medium of A2058 cells. A direct correlation between TPA- and TNF-alpha-mediated promoter stimulation of the 92-kD type IV collagenase gene and its expression was also demonstrated in the human fibrosarcoma HT1080 cells. Interleukin-1 alpha failed to induce 92-kD gene promoter activity and type IV collagenase expression in melanoma and fibrosarcoma cell lines. Our data demonstrated that TPA- and TNF-alpha-induced 92-kD type IV collagenase promoter stimulation leads to a proportional increase of enzyme expression and secretion and thus could contribute to the activation of the invasive phenotype