Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

Jiang, Jie-Gen; Chen, Qiuyan; Bell, Aaron; Zarnegar, Reza

doi:10.1038/sj.onc.1201152

Cited by 37 publications

(26 citation statements)

References 40 publications

(58 reference statements)

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“…DNase I footprinting using intact nuclei from regenerating mouse liver identi®ed several hypersensitive sites within the upstream region of the HGF promoter, one of which was mapped to a region approximately 0.3 kb from the transcription initiation site (Bell et al, 1998). Similar results were obtained when intact nuclei from NIH3T3 cells were subjected to DNase I footprinting (Jiang et al, 1997b). In vitro analysis of the HGF promoter using transient transfection of HGF-promoter constructs into NIH3T3 ®broblasts showed that a regulatory element(s) is present from 0.2 to 0.3 kb upstream of the promoter (Liu et al, 1994;Plashke-Schlutter et al, 1995).…”

supporting

confidence: 60%

“…Toward this, our laboratory as well as others have shown that several potential transcriptional regulatory elements are present in the 5'-¯anking region of the HGF gene promoter (Aravamundan et al, 1993;Liu et al, 1994;Okajima et al, 1993;Plaschke-Schlutter et al, 1995). Our previous studies demonstrated that several transcription factors, including estrogen receptor (ER) and chicken ovalbumin upstream promoter transcription factor (COUP-TF) (Jiang et al, 1997a), C/EBP (Jiang and Zarnegar, 1997), and Sp1 (Jiang et al, 1997b), bind to the HGF promoter region and regulate its activity.…”

mentioning

confidence: 96%

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The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene

2000

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supporting

confidence: 60%

mentioning

confidence: 96%

The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene

2000

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“…This inhibition may be caused by steric hindrance rather than by direct competition, since the binding sites of AP-1 and Sp-1 are separated by approximately 30 bp. Sp proteins may dominate because of their higher amount/anity than AP-1, since we found that Sp-3 also binds to the Sp-1 site and since it is reported that Sp-3 may regulate gene expression in a positive as well as negative manner (Jiang et al, 1997). It is possible that Ap-1 binding dampens the negative eects of Sp-3 and further induces c-met gene expression.…”

Section: Resultsmentioning

confidence: 84%

Transcriptional activation of the Hepatocyte Growth Factor receptor (c-met) gene by its ligand (Hepatocyte Growth Factor) is mediated through AP-1

2000

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Hepatocyte Growth Factor (HGF) exerts its biological eects 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) identi®ed the responsive element as an activated protein-1 (AP-1) binding site (TGAGTCA) within the c-met core promoter region at position 7158 to 7152. The c-met AP-1 element binds speci®cally to AP-1 protein as veri®ed 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 7124) 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 cmet promoter constructs resulted in stimulation of c-met promoter activity. We found that transactivation of the cmet 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.

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“…Ctr, mRNA in untreated cells maintained in culture medium for 24 h. cells. Sp1 and Sp3, like other members of the Sp family, recognize the G ϩ C-rich repeats (47) and act as positive transcription factors on a wide variety of cellular genes (48), including collagen genes (49 -51).…”

Section: Discussionmentioning

confidence: 99%

Sp1 and Sp3 Transcription Factors Mediate Malondialdehyde-induced Collagen α1(I) Gene Expression in Cultured Hepatic Stellate Cells

Garcia‐Ruiz

Torre

Díaz

et al. 2002

Journal of Biological Chemistry

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Malondialdehyde, the end product of lipid peroxidation, has been shown to stimulate collagen ␣1(I) (Col1a1) gene expression. However, mechanisms of this effect are unclear. The purpose of this study was to clarify these mechanisms. Rat hepatic stellate cells were cultured in the presence of 200 M malondialdehyde, and the effects on collagen gene expression and the binding of nuclear proteins to the col1a1 promoter were analyzed. Malondialdehyde treatment induced an increase in the cellular levels of col1a1 mRNA that was abrogated by pretreating cells with cycloheximide, p-hydroxymercuribenzoate, pyridoxal 5-phosphate, and mithramycin. Transient transfections showed that malondialdehyde exerted its effect through regulatory elements located between ؊220 and ؊110 bp of the col1a1 promoter. Gel retardation assays demonstrated that malondialdehyde increased the binding of nuclear proteins to two elements located between ؊161 and ؊110 bp of the col1a1 promoter. These bindings were supershifted with Sp1 and Sp3 antibodies. Finally, malondialdehyde increased cellular levels of the Sp1 and Sp3 proteins and Sp1 mRNA. Our data indicated that treatment of hepatic stellate cells with malondialdehyde stimulated col1a1 gene expression by inducing the synthesis of Sp1 and Sp3 and their binding to two regulatory elements located between ؊161 and ؊110 bp of the col1a1 promoter.Lipid peroxidation by-products, particularly reactive aldehydes, such as malondialdehyde (MDA) 1 and 4-hydroxy-2-nonenal (4HNE), have been incriminated in the pathogenesis of liver fibrosis. Thus, Chojkier et al.(1) first showed that MDA increased significantly the collagen ␣1(I) (Col1a1) mRNA in cultured human fetal fibroblasts, and Maher et al. (2) found that collagen synthesis doubled in response to MDA in rat kidney fibroblasts. Likewise, Parola et al. (3,4) showed that 4HNE and other 4-hydroxy-2,3-alkenals, aldehydic end products of lipid peroxidations, were able to stimulate col1a1 gene expression and collagen synthesis in cultured hepatic stellate cells (HSC). Similar results have been reported by Tsukamoto and co-workers (5, 6), who also observed a significant correlation between the liver MDA and 4HNE levels and the hepatic collagen accumulation in a rat model of alcoholic liver disease.Mechanisms by which these reactive aldehydes induce col1a1 gene expression and synthesis are still unclear. However, a number of studies have provided evidence supporting the role of aldehyde-protein adducts in the regulation of col1a1 gene expression. These aldehydes are known to react with sulfhydryl or amino groups to form aldehyde-protein adducts (7). These adducts have been found in alcoholic liver disease (8, 9) and other clinical conditions of chronic liver injury associated with active fibrogenesis, as well as in animal models of lipid peroxidation (6, 10 -14). Moreover, antioxidant treatment significantly decreased the production of these adducts and prevented the fibrogenesis cascade (10, 13, 15). The purpose of this study was to clarify the mechanisms ...

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Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

Cited by 37 publications

References 40 publications

The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene

The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene

Transcriptional activation of the Hepatocyte Growth Factor receptor (c-met) gene by its ligand (Hepatocyte Growth Factor) is mediated through AP-1

Sp1 and Sp3 Transcription Factors Mediate Malondialdehyde-induced Collagen α1(I) Gene Expression in Cultured Hepatic Stellate Cells

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