Transcriptional activation of the Hepatocyte Growth Factor receptor (c-met) gene by its ligand (Hepatocyte Growth Factor) is mediated through AP-1
- 24 February 2000
- journal article
- Published by Springer Nature in Oncogene
- Vol. 19 (9), 1132-1137
- https://doi.org/10.1038/sj.onc.1203404
Abstract
Hepatocyte Growth Factor (HGF) exerts its biological effects via binding and activating a transmembrane protein tyrosine kinase receptor known as c-Met. Previous studies from our laboratory demonstrated that c-met gene expression is inducible by its own ligand (HGF). However, the molecular mechanism(s) involved in this process are unknown. The present study was carried out to address this question. Transfection of various c-met-CAT promoter constructs into the mouse hepatocellular carcinoma cell line Hepa 1-6 in combination with electrophoretic mobility shift assays (EMSA) identified the responsive element as an activated protein-1 (AP-1) binding site (TGAGTCA) within the c-met core promoter region at position -158 to -152. The c-met AP-1 element binds specifically to AP-1 protein as verified by supershift assays. EMSA studies and mutational analyses of the promoter region also revealed that the members of the Sp family of transcription factors (Sp-1 and Sp-3) bind to the c-met Sp-1 element (located at position -124) which is adjacent to the AP-1 site. We show that Sp binding dampens binding of AP-1 to its cognate site in the c-met promoter region. Stimulation of Hepa 1-6 cells with HGF resulted in a rapid and dramatic enhancement of the AP-1 binding activity as well as an overall increase in the level of AP-1 protein. Cotransfection of AP-1 expression vectors (c-Fos plus c-Jun) with c-met promoter constructs resulted in stimulation of c-met promoter activity. We found that transactivation of the c-met promoter by AP-1 can be blocked by Curcumin, an inhibitor of AP-1. Moreover, we found that the induction of the endogenous c-met gene by HGF is inhibited by the addition of Curcumin. The results demonstrate that the HGF-induced transcription of the c-met gene by HGF is, at least in part, due to activation of the AP-1 pathway.Keywords
This publication has 30 references indexed in Scilit:
- The five amino acid-deleted isoform of hepatocyte growth factor promotes carcinogenesis in transgenic miceOncogene, 1999
- The mutationally activated Met receptor mediates motility and metastasisProceedings of the National Academy of Sciences, 1998
- Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcuminOncogene, 1998
- Role of Activating Protein-1 in the Regulation of the Vascular Cell Adhesion Molecule-1 Gene Expression by Tumor Necrosis Factor-αJournal of Biological Chemistry, 1998
- Sp1 Is Required for the Early Response of α2(I) Collagen to Transforming Growth Factor-β1Journal of Biological Chemistry, 1997
- Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell linesHepatology, 1997
- Transcription factor requirements for U2 snRNA-encoding gene activation in B lymphoid cellsGene, 1991
- Mithramycin inhibits SP1 binding and selectively inhibits transcriptional activity of the dihydrofolate reductase gene in vitro and in vivo.JCI Insight, 1991
- Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells.Proceedings of the National Academy of Sciences, 1991
- Identification of the Hepatocyte Growth Factor Receptor As the c- met Proto-Oncogene ProductScience, 1991