Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells.
92-kDa Type IV collagenase, a member of matrix metalloproteinases, is believed to play a critical role in physiological tissue-remodeling processes and also in many pathological conditions such as tumor invasion. We analyzed the 5'-flanking sequence of the 92 kDa type IV collagenase gene that controls the expression of the gene by ligating it to the chloramphenicol acetyltransferase gene. Deletion and mutation analysis revealed that three motifs, homologous to the binding sites for AP-1, NF-kappa B, and Sp-1 proteins, contributed positively to induction by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and tumor necrosis factor alpha (TNF alpha). The AP-1 site was indispensable but not sufficient for the induction and required synergistic cooperation with either the kappa B or the Sp-1 site. In OST cells, a nuclear factor which bound to Sp-1 was constitutively expressed, and those bound to AP-1 and kappa B elements were rapidly induced by TNF alpha treatment. Comparison of the findings with those for the promoters of other TPA-inducible matrix metalloproteinases, interstitial collagenase and stromelysin 1, revealed that the signal to the AP-1 sites is common for the TPA-inducibility of the genes but that the signals to the kappa B or Sp-1 sites, which are not present in interstitial collagenase and stromelysin 1 promoters, are the unique determinant for the inducibility of the 92 kDa type IV collagenase gene.
Sato
H
H
Department of Molecular Virology and Oncology, Kanazawa University, Ishikawa, Japan.
Seiki
M
M
D001483:Base Sequence; D001665:Binding Sites; D017364:Collagenases / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020780:Matrix Metalloproteinase 9; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000494:pharmacology; D016385:TATA Box; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate