The Transcription Factor EGR-1 Suppresses Transformation of Human Fibrosarcoma HT1080 Cells by Coordinated Induction of Transforming Growth Factor-β1, Fibronectin, and Plasminogen Activator Inhibitor-1
| Autor: | Jin Yao, Eileen D. Adamson, Chaoting Liu, Dan Mercola, Ian de Belle, Ruo-Pan Huang |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Fibrosarcoma
Transfection Biochemistry Immediate-Early Proteins Oligodeoxyribonucleotides Antisense chemistry.chemical_compound Transforming Growth Factor beta Plasminogen Activator Inhibitor 1 Cell Adhesion Tumor Cells Cultured Humans Secretion Promoter Regions Genetic Autocrine signalling Molecular Biology Early Growth Response Protein 1 biology Zinc Fingers Cell Biology Molecular biology Fibronectins DNA-Binding Proteins Gene Expression Regulation Neoplastic body regions Fibronectin Cell Transformation Neoplastic chemistry Plasminogen activator inhibitor-1 biology.protein HT1080 Oligopeptides Plasminogen activator hormones hormone substitutes and hormone antagonists Transcription Factors Transforming growth factor |
| Zdroj: | Journal of Biological Chemistry. 274:4400-4411 |
| ISSN: | 0021-9258 |
| Popis: | Re-expression of EGR-1 in fibrosarcoma HT1080 suppresses transformation including tumorigenicity (Huang, R.-P., Liu, C., Fan, Y., Mercola, D., and Adamson, E. (1995) Cancer Res. 55, 5054-5062) owing in part to up-regulation of the transforming growth factor (TGF)-beta1 promoter by EGR-1 which suppresses growth by an autocrine mechanism (Liu, C., Adamson, E., and Mercola, D. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 11831-11836). Here we show that enhanced cell attachment contributes to the suppression via increased secretion of fibronectin (FN) and also of plasminogen activator inhibitor-1 (PAI-1). The secretion of FN and PAI-1 is strongly correlated with EGR-1 expression (RPEARSON = 0.971 and 0. 985, respectively). Addition of authentic TGF-beta1 to parental cells greatly stimulated secretion of PAI-1 but not FN, whereas addition of TGF-beta antibody or lipofection with specific antisense TGF-beta1 oligonucleotides to EGR-1-regulated cells completely inhibits the secretion of PAI-1 but not FN. However, in gel mobility shift assays pure EGR-1 or nuclear extracts of EGR-1-regulated cells specifically bind to two GC-rich elements of the human FN promoter at positions -75/-52 and -4/+18, indicating that the increased secretion of FN is likely due to direct up-regulation by EGR-1. Moreover, adhesion was greatly enhanced in EGR-1-regulated cells and was reversed by treatment with Arg-Gly-Asp (RGD) or PAI-1 antibody indicating that the secreted proteins are functional. We conclude that EGR-1 regulates the coordinated expression of gene products important for cell attachment ("oikis" factor) and normal growth control. |
| Databáze: | OpenAIRE |
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