Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo

Blood. 2009 Dec 24;114(27):5557-66. doi: 10.1182/blood-2009-05-220434. Epub 2009 Oct 12.


Vascular endothelial growth factor receptor 1 (VEGFR1) is a marker for endothelial-specific gene expression. We previously reported that the human VEGFR1 promoter (between -748 and +284) contains information for expression in the intact endothelium of transgenic mice. The objective of this study was to dissect the cis-regulatory elements underlying VEGFR1 promoter activity in vitro and in vivo. In primary endothelial cells, binding sites for E74-like factor 1 (ELF-1; between -49 and -52), cyclic adenosine monophosphate response element binding (CREB; between -74 and -81), and early growth response factor 1/3 (EGR-1/3; between -16 to -25) were shown to play a positive role in gene transcription, whereas a putative E26 transformation-specificsequence (ETS) motif between -36 and -39 had a net negative effect on promoter activity. When targeted to the Hprt locus of mice, mutations of the ELF-1 binding site and the CRE element reduced promoter activity in the embryonic vasculature and resulted in a virtual loss of expression in adult endothelium. Postnatally, the EGR binding site mutant displayed significantly reduced promoter activity in a subset of vascular beds. In contrast, mutation of the -39 ETS site resulted in increased LacZ staining in multiple vascular beds. Together, these results provide new insights into the transcriptional regulatory mechanisms of VEGFR1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • Binding Sites / physiology
  • CREB-Binding Protein / metabolism*
  • Cells, Cultured
  • Early Growth Response Protein 1 / metabolism
  • Early Growth Response Protein 3 / metabolism
  • Early Growth Response Transcription Factors / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Female
  • Gene Expression Regulation / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic / genetics*
  • Protein Binding
  • Sequence Homology, Nucleic Acid
  • Transcription Factors / metabolism*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics*


  • EGR1 protein, human
  • EGR3 protein, human
  • ELF1 protein, human
  • Early Growth Response Protein 1
  • Early Growth Response Transcription Factors
  • Nuclear Proteins
  • Transcription Factors
  • Early Growth Response Protein 3
  • CREB-Binding Protein
  • Vascular Endothelial Growth Factor Receptor-1