title: Regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in MCF-7 cells: comparison with regulatory mechanisms of pS2 expression.
abstract: Regulation of two genes involved in tumor invasion, the matrix metalloproteinase (MMP)-1 and the tissue inhibitor of MMP (TIMP)-1, by activators of protein kinase C (PKC) or protein kinase A (PKA) was studied in MCF-7 mammary adenocarcinoma cells. The basal mRNA expression was undetectable 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 with a high expression of MMP-1 mRNA, as well as an induction of the level of TIMP-1 mRNA (5- to 10-fold). In the presence of actinomycin D (AMD, 4.0 microM), an inhibitor of transcription, these stimulatory effects of TPA were abolished. Similar responses were observed when protein synthesis was inhibited by cycloheximide (CHX, 50 microM). In the presence of the cyclic AMP (cAMP) analogue N6-benzoyl (N6-Bzl)-cAMP (500 microM), the MMP-1 mRNA was unaffected and still below the level of detection, whereas a non-significant increase (< 2-fold) in TIMP-1 mRNA was observed. The level of pS2 mRNA, of which the induction by TPA in MCF-7 cells is a primary transcriptional event, was up-regulated (10- to 15-fold) by TPA (100 nM), whereas a much weaker increase (2- to 3-fold) was observed by treatment with N6-Bzl-cAMP (500 microM). Again, these stimulatory effects were counteracted by AMD (4.0 microM) and CHX (50 microM). These data suggest that activation of PKC but not of PKA may induce transcription of MMP-1 and TIMP-1, possibly by the synthesis of transcription factor(s), in transformed cells of epithelial origin.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo. a.h.ree@dnr.uio.no
authors.forename: A H
authors.initials: AH
authors.lastname: Ree
authors.forename: G M
authors.initials: GM
authors.lastname: Maelandsmo
authors.forename: O
authors.initials: O
authors.lastname: Fodstad
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D017364:Collagenases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020781:Matrix Metalloproteinase 1; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins; D012333:RNA, Messenger; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D014158:Transcription, Genetic / Q000187:drug effects; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D006023:Glycoproteins; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D012333:RNA, Messenger; C051838:TFF1 protein, human; D019714:Tissue Inhibitor of Metalloproteinases; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; C050086:N(6)-benzoyl-cyclic AMP; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D017364:Collagenases; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate