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.

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