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  • Original Paper
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Runx1 promotes angiogenesis by downregulation of insulin-like growth factor-binding protein-3

Oncogene volume 24, pages 1129–1137 (2005)Cite this article

Abstract

Mouse embryos lacking the Runx1 transcription factor exhibit an angiogenic defect accompanied by the absence of hematopoietic stem cells (HSCs). To ask whether Runx1 plays a direct role in angiogenesis, we established a novel endothelial progenitor cell line, designated AEL-ΔR1, from the aorta-gonad-mesonephros (AGM) region of Runx1-null mouse. We introduced Runx1 cDNA into AEL-ΔR1 cells under the doxycycline-inducible promoter. The ability of AEL-ΔR1 cells to form vascular networks on matrigel was highly enhanced by the restored expression of Runx1. By molecular comparison of mRNAs in AEL-ΔR1 cells before and after the induction of Runx1, we found that mRNA expression of insulin-like growth factor-binding protein 3 (IGFBP-3) is downregulated by Runx1. Gel retardation and reporter assays revealed that Runx1 binds to the promoter region of mouse IGFBP-3 gene and represses its transcription. When IGFBP-3 was exogenously added in the matrigel assay, the angiogenesis-enhancing activity of Runx1 was suppressed in a dose-dependent manner. These results demonstrate that Runx1 is directly involved in angiogenesis by repression of IGFBP-3 mRNA expression.

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Acknowledgements

We thank Dr I Kitabayashi (National Cancer Center Research Institute, Tokyo) for the pCCP1-Luc vector, Dr S Nishikawa (RIKEN, Kobe) for anti-VE-cadherin antibody, Professor T Kitamura (University of Tokyo) for the pMY vector/PLAT-E retrovirus packaging cell line, Dr N Drinkwater (University of Wisconsin Medical School) for the pMESVts retrovirus vector, and Professor M Hagiwara (Tokyo Medical and Dental University) for the pLRT retrovirus vector. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Research Grant from the Human Frontier Science Program, and a Research grant from the Human Science Foundation.

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  1. Ken Iwatsuki

    Present address: Department of Physiology and Biophysics, The Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY, 10029, USA

Authors and Affiliations

  1. Department of Tumor Biochemistry, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan

    Ken Iwatsuki, Kiyoko Tanaka, Tsuyoshi Kaneko, Ritsuko Kazama, Shiki Okamoto, Yuki Nakayama & Takahiko Hara

  2. Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore, 117609, Singapore

    Yoshiaki Ito

  3. Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Masanobu Satake & Toshio Watanabe

  4. Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan

    Shin-Ichiro Takahashi

  5. Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan

    Atsushi Miyajima

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Correspondence to Takahiko Hara.

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Iwatsuki, K., Tanaka, K., Kaneko, T. et al. Runx1 promotes angiogenesis by downregulation of insulin-like growth factor-binding protein-3. Oncogene 24, 1129–1137 (2005). https://doi.org/10.1038/sj.onc.1208287

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