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

Ken Iwatsuki; Kiyoko Tanaka; Tsuyoshi Kaneko; Ritsuko Kazama; Shiki Okamoto; Yuki Nakayama; Yoshiaki Ito; Masanobu Satake; Shin-Ichiro Takahashi; Atsushi Miyajima; Toshio Watanabe; Takahiko Hara

doi:10.1038/sj.onc.1208287

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

Oncogene. 2005 Feb 10;24(7):1129-37. doi: 10.1038/sj.onc.1208287.

Authors

Ken Iwatsuki¹, Kiyoko Tanaka, Tsuyoshi Kaneko, Ritsuko Kazama, Shiki Okamoto, Yuki Nakayama, Yoshiaki Ito, Masanobu Satake, Shin-Ichiro Takahashi, Atsushi Miyajima, Toshio Watanabe, Takahiko Hara

Affiliation

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.

PMID: 15592512
DOI: 10.1038/sj.onc.1208287

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-DeltaR1, from the aorta-gonad-mesonephros (AGM) region of Runx1-null mouse. We introduced Runx1 cDNA into AEL-DeltaR1 cells under the doxycycline-inducible promoter. The ability of AEL-DeltaR1 cells to form vascular networks on matrigel was highly enhanced by the restored expression of Runx1. By molecular comparison of mRNAs in AEL-DeltaR1 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Proliferation
Collagen / chemistry
Core Binding Factor Alpha 2 Subunit
DNA, Complementary / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
DNA-Binding Proteins / physiology*
Down-Regulation / genetics*
Doxycycline / pharmacology
Drug Combinations
Electrophoretic Mobility Shift Assay
Endothelium, Vascular / chemistry
Endothelium, Vascular / physiology*
Gene Expression / genetics
Insulin-Like Growth Factor Binding Protein 3 / genetics*
Laminin / chemistry
Mice
Mice, Knockout
Neovascularization, Physiologic / genetics*
Neovascularization, Physiologic / physiology
Promoter Regions, Genetic / drug effects
Promoter Regions, Genetic / genetics
Proteoglycans / chemistry
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins / physiology*
RNA, Messenger / analysis
RNA, Messenger / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Repressor Proteins / physiology*
Stem Cells / chemistry
Stem Cells / physiology
Transcription Factors / genetics
Transcription Factors / metabolism
Transcription Factors / physiology*

Substances

Core Binding Factor Alpha 2 Subunit
DNA, Complementary
DNA-Binding Proteins
Drug Combinations
Insulin-Like Growth Factor Binding Protein 3
Laminin
Proteoglycans
Proto-Oncogene Proteins
RNA, Messenger
Repressor Proteins
Runx1 protein, mouse
Transcription Factors
matrigel
Collagen
Doxycycline