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The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element

Oncogene volume 23, pages 679–686 (2004)Cite this article

Abstract

We found that human melanoma SEKI and neuroepithelioma NAGAI cells, which are known to secrete high concentrations of leukemia inhibitory factor (LIF), also secrete high levels of hepatocyte growth factor (HGF). We therefore examined the role of LIF in HGF expression and examined the human HGF promoter. The expression of both LIF and HGF mRNA is very low in HEK293 cells. Treatment of these cells with LIF stimulated the expression of HGF mRNA. The cis-acting regulatory element of the HGF promoter in SEKI and 293 cells was analysed by means of a transient expression assay. By deletion analysis, we showed that the region comprising the −181 to −73 bp was required for full activity of the HGF promoter in SEKI cells and for LIF responsiveness of 293 cells. This region contains putative consensus sequences for the Stat and NF-IL6 (C/EBP β) transcription factors. The activity of the HGF promoter was abolished by mutation of the Stat site at −99/−91, while the activity only slightly decreased on mutation of the NF-IL6 site. Treatment with anti-LIF antibodies or interruption of Stat3 signaling by dominant-negative Stat3 also reduced the HGF promoter activity. Stat3 activation was constitutive in SEKI cells and induced on treatment of 293 cells with LIF. These results suggest that cytokines, growth factors and oncogenes (v-Src, etc.) that activate Stat3 are important regulators of HGF expression.

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References

  • Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T and Kishimoto T . (1990). EMBO J., 9, 1897–1906.

  • Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M and Kishimoto T . (1994). Cell, 77, 63–71.

  • Auernhammer CJ and Melmed S . (2000). Endocr. Rev., 21, 313–345.

  • Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T and Oliver JA . (1999). Cell, 99, 377–386.

  • Bowman T, Garcia R, Turkson J and Jove R . (2000). Oncogene, 19, 2474–2488.

  • Bromberg J . (2002). J. Clin. Invest., 109, 1139–1142.

  • Ehret GB, Reichenbach P, Schindler U, Horvath CM, Fritz S, Nabholz M and Bucher P . (2001). J. Biol. Chem., 276, 6675–6688.

  • Horvath CM, Wen Z and Darnell Jr JE . (1995). Genes Dev., 15, 984–994.

  • Hung W and Elliott B . (2001). J. Biol. Chem., 276, 12395–12403.

  • Iseki H, Kajimura N, Ohue C, Tanaka R, Akiyama Y and Yamaguchi K . (1995). Jpn. J. Cancer Res., 86, 562–567.

  • Jiang JG and Zarnegar R . (1997). Mol. Cell. Biol., 17, 5758–5770.

  • Kamohara H, Sakamoto K, Ishiko T, Mita S, Masuda Y, Abe T and Ogawa M . (1994). Res. Commun. Mol. Pathol. Pharmacol., 85, 131–140.

  • Li M, Sendtner M and Smith A . (1995). Nature, 378, 724–727.

  • Liu Y, Michalopoulos GK and Zarnegar R . (1994). J. Biol. Chem., 269, 4152–4160.

  • Lowe DG, Nunes W, Bombara M, McCabe S, Ranges GE, Henzel W, Tomida M, Yamamoto-Yamaguchi Y, Hozumi M and Goeddel DV . (1989). DNA, 8, 351–359.

  • Maina F and Klein R . (1999). Nat. Neurosci., 2, 213–217.

  • Matsumoto K and Nakamura T . (1996). J. Biochem. (Tokyo), 119, 591–600.

  • Miyazawa K, Kitamura A and Kitamura N . (1991). Biochemistry, 30, 9170–9176.

  • Nakamura T, Matsumoto K, Kiritoshi A, Tano Y and Nakamura T . (1997). Cancer Res., 57, 3305–3313.

  • Nakamura T, Nawa K and Ichihara A . (1984). Biochem. Biophys. Res. Commun., 122, 1450–1459.

  • Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R and Yu H . (2002). Oncogene, 21, 2000–2008.

  • O'Farrell AM, Liu Y, Moore KW and Mui AL . (1998). EMBO J., 17, 1006–1018.

  • Santos OF, Barros EJ, Yang XM, Matsumoto K, Nakamura T, Park M and Nigam SK . (1994). Dev. Biol., 163, 525–529.

  • Schmelzer CH, Harris RJ, Butler D, Yedinak CM, Wagner KL and Burton LE . (1993). Arch. Biochem. Biophys., 302, 484–489.

  • Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E and Birchmeier C . (1995). Nature, 373, 699–702.

  • Seidel HM, Milocco LH, Lamb P, Darnell Jr JE, Stein RB and Rosen J . (1995). Proc. Natl. Acad. Sci. USA, 92, 3041–3045.

  • Tamura M, Arakaki N, Tsubouchi H, Takada H and Daikuhara Y . (1993). J. Biol. Chem., 268, 8140–8145.

  • Tomida M, Yamamoto-Yamaguchi Y and Hozumi M . (1984). FEES Lett., 178, 291–296.

  • Tomida M, Yamamoto-Yamaguchi Y, Hozumi M, Holmes W, Lowe DG and Goeddel DV . (1990). FEES Lett., 268, 261–264.

  • Tomida M, Heike T and Yokota T . (1999). Blood, 93, 934–941.

  • Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T and Kitamura N . (1995). Nature, 373, 702–705.

  • Wagner BJ, Hayes TE, Hoban CJ and Cochran BH . (1990). EMBO J., 9, 4477–4484.

  • Ware CB, Horowitz MC, Renshaw BR, Hunt JS, Liggitt D, Koblar SA, Gliniak BC, McKenna HJ, Papayannopoulou T, Thoma B, Cheng L, Donovan PJ, Peschon JJ, Bartlett PF, Willis CR, Wright BD, Carpenter MK, Davison BL and Gearing DP . (1995). Development, 121, 1283–1299.

  • Weidner KM, Arakaki N, Hartmann G, Vandekerckhove J, Weingart S, Rieder H, Fonatsch C, Tsubouchi H, Hishida T, Daikuhara Y and Birchmeier W . (1991). Proc. Natl. Acad. Sci. USA, 88, 7001–7005.

  • Woolf AS, Kolatsi-Joannou M, Hardman P, Andermarcher E, Moorby C, Fine LG, Jat PS, Noble MD and Gherardi E . (1995). J. Cell Biol., 128, 171–184.

  • Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J and Jove R . (1995). Science, 269, 81–83.

  • Zhong Z, Wen Z and Darnell Jr JE . (1994). Science, 264, 95–98.

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Acknowledgements

We wish to thank Dr Takashi Yokota, Graduate School of Medical Science, Kanazawa University, for providing the dominant-negative Stat3B construct. This work was supported in part by the Project, Saitama Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence, JST.

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  1. Research Division, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan

    Mikio Tomida & Takeshi Saito

  2. REDS Group (Saitama Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence, JST), Saitama Small Enterprise Promotion Corporation, SKIP city, Kawaguchi, 333-0844, Japan

    Takeshi Saito

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Correspondence to Mikio Tomida.

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Tomida, M., Saito, T. The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element. Oncogene 23, 679–686 (2004). https://doi.org/10.1038/sj.onc.1207190

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