REGULATION OF MATRIX METALLOPROTEINASE-1 AND TISSUE INHIBITOR OF METALLOPROTEINASE-1 IN MCF-7 CELLS - COMPARISON WITH REGULATORY MECHANISMSOF PS2 EXPRESSION

Regulation of two genes involved in tumor invasion, the matrix metallo proteinase (MMP)-1 and the tissue inhibitor of MMP (TIMP)-1, by activa tors of protein kinase C (PKC) or protein kinase A (PKA) was studied i n MCF-7 mammary adenocarcinoma cells, The basal mRNA expression was un detectable for MMP-1 and low for TIMP-1, Treatment of MCF-7 cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (100 nM) was associated,vith a high expression of MMP-1 mRNA, as well as an in duction of the level of TIMP-1 mRNA (5- to 10-fold), In the presence o f actinomycin D (AMD, 4.0 mu M), an inhibitor of transcription, these stimulatory effects of TPA were abolished, Similar responses were obse rved when protein synthesis was inhibited by cycloheximide (CHX, 50 mu M) In the presence of the cyclic AMP (cAMP) analogue N-6-benzoyl (N-6 -Bzl)-cAMP (500 mu M), the MMP-1 mRNA was unaffected and still below t he level of detection, whereas a non-significant increase (< 2-fold) i n TIMP-1 mRNA was observed, The level of pS2 mRNA, of which the induct ion by TPA in MCF-7 cells is a primary transcriptional event, was up-r egulated (10- to 15-fold) by TPA (100 nM), whereas a much weaker incre ase (2- to 3-fold) was observed by treatment with N-6-Bzl-cAMP (500 mu M), Again, these stimulatory effects were counteracted by AMD (4.0 mu M) and CHX (50 mu M). These data suggest that activation of PKC but n ot of PKA may induce transcription of MMP-1 and TIMP-1, possibly by th e synthesis of transcription factor(s), in transformed cells of epithe lial origin.