Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth

Nat Med. 2003 Aug;9(8):1026-32. doi: 10.1038/nm905. Epub 2003 Jul 20.


Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5' untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms
  • Cell Division / physiology
  • Cell Movement / physiology
  • DNA, Catalytic / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Early Growth Response Protein 1
  • Endothelial Growth Factors / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Female
  • Fibroblast Growth Factor 2 / metabolism*
  • Humans
  • Immediate-Early Proteins*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lymphokines / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Microtubules / metabolism
  • Neoplasm Transplantation / pathology*
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / pathology*
  • Neovascularization, Pathologic*
  • Neovascularization, Physiologic*
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • DNA, Catalytic
  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Egr1 protein, rat
  • Endothelial Growth Factors
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2