Okadaic acid-elicited transcriptional activation of collagenase gene expression in HT-1080 fibrosarcoma cells is mediated by JunB.
Okadaic acid (OA) is a novel, non-phorbol ester-type tumor promoter, which is a specific inhibitor of protein phosphatases 1 and 2A. Treatment of human fibrosarcoma HT-1080 cells with OA resulted in induction of collagenase and stromelysin-1 mRNA levels, while mRNA levels for tissue inhibitor of metalloproteinases-1 were enhanced to a lesser extent. Induction of collagenase and stromelysin-1 mRNA levels was dependent on protein synthesis. Exposure of HT-1080 cells to OA resulted in marked and persistent induction of junB, junD, and c-fos mRNA levels up to 24 h, while c-jun mRNA levels were only slightly elevated. In transiently transfected HT-1080 cells, OA-elicited activation of a 3.8-kilobase collagenase promoter/reporter gene construct was entirely dependent on junB expression, as determined by cotransfection with a junB antisense expression construct. Overexpression of JunB in HT-1080 cells enhanced collagenase promoter activity by 10-fold, and OA augmented trans-activation of collagenase promoter by c-Jun and JunB. The results indicate that induction of collagenase gene expression by OA is mediated by enhanced JunB expression, as well as enhanced trans-activating capacity of AP-1 complexes containing c-Jun and JunB. These results also suggest that selective overexpression of junB may enhance invasive and metastatic potential of neoplastic cells.
Department of Dermatology, University of Turku, Finland.
J
J
Westermarck
J
J
Lohi
J
J
Keski-Oja
V M
VM
Kähäri
D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005354:Fibrosarcoma / Q000201:enzymology; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D018808:Transcription Factor AP-1 / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D004988:Ethers, Cyclic; D006023:Glycoproteins; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D018808:Transcription Factor AP-1; D019319:Okadaic Acid; D003907:Dexamethasone; D010749:Phosphoprotein Phosphatases; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D013755:Tetradecanoylphorbol Acetate