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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

Oncogene volume 19, pages 2786–2790 (2000)Cite this article

Abstract

Hepatocyte growth factor (HGF) is an important multifunctional cytokine whose gene expression is regulated mainly at the transcriptional level. Previous studies using transgenic mice as well as in vitro analyses showed that a potential regulatory element(s) exists between −260 to −230 bp in the upstream region of the HGF gene promoter. In the present study, we have discovered that this region is a composite site through which members of the nuclear factor 1 (NF1) and upstream stimulatory factor (USF) families bind to and regulate HGF gene transcription. Gel mobility shift and supershift assays revealed that USF and NF1 have high binding affinity for this region and that the binding sites of the two different transcription factor families overlap. Functional studies showed that NF1 suppresses HGF gene promoter activity and that USF has an activating function. We found that the NF1/X and NF1/Red1 isoforms strongly suppressed HGF promoter activity while the NF1/L variant had no obvious effects. USF1, but not USF2, of the USF family stimulated HGF gene promoter activity. More interestingly, during liver regeneration after partial hepatectomy, a process which activates the HGF gene, we noted that the binding activity of USF to the HGF promoter element increased while that of NF1 decreased. These data provide insight into the molecular mechanisms that govern HGF gene transcription.

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Acknowledgements

We thank Dr MA Thompson for providing us with the psPUTK-NF1/L expression vector; Dr M Sawadogo for USF-related expression vectors; and Dr N Tanese for the antibody against NF1. We are thankful to Dr GK Michalopoulos for many valuable discussions and his continuous enthusiasm during the course of this work. We also thank Dr MC DeFrances for critical review of this manuscript. This work was supported by grants from NIEHS (R01ES 06109) and American Cancer Society (RPG-91-009-10-CNE) awarded to R Zarnegar.

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Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburth, 15261, Pennsylvania, PA, USA

    Jie-Gen Jiang & Reza Zarnegar

  2. Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, 23298, Virginia, VA, USA

    Bin Gao

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  1. Jie-Gen Jiang
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  2. Bin Gao
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Jiang, JG., Gao, B. & Zarnegar, R. 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. Oncogene 19, 2786–2790 (2000). https://doi.org/10.1038/sj.onc.1203581

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