The tumor promoter, TPA, was observed to have divergent effects on the expression of two major gelatinolytic metalloproteinases (gelatinases), i.e., a 67 kDa, found in both normal and neoplastic cells, and a 92 kDa gelatinase found in neoplastic and inflammatory cells. The 67 kDa gelatinase was not, or minimally, stimulated by TPA. However, a 92 kDa gelatinase was stimulated by TPA in different tumor lines. A striking TPA-mediated induction of the 92 kDa gelatinase was observed in a neuroblastoma (SK-N-SH) and an embryonal carcinoma (Tera-2). Cell lines, such as a breast carcinoma (MDA-MB-231) with a high 92 kDa gelatinolytic activity showed little, or no, response to TPA. TPA activates protein kinase C (PKC) and has been reported to induce activation of the proto-oncogenes jun and fos in certain cell lines, which, in turn, form a complex capable of activating AP-1 responsive genes. Two members of the metalloproteinase family, i.e., type I collagenase and stromelysin have already been shown to have TPA responsive elements with AP-1 binding DNA sequence. Analysis of nuclear protein jun/fos complexes prepared from selected cell lines used in this study suggested that a correlation exists between binding activity and the presence or induction of the 92 kDa gelatinase. For example, the MRC-5 fibroblast cell line which has no 92 kDa gelatinase activity before or after TPA treatment showed no AP-1 binding activity, but a marked induction of the 92 kDa gelatinolytic activity observed in the SK-N-SH tumor cell line was paralleled by an increase in AP-1 binding activity. CDNA clones were isolated for both gelatinases. Presently it is being tested whether the TPAmediated effect on the expression of the two gelatinases corresponds to their gene expression in Northern blots.
