Endoglin expression in the endothelium is regulated by Fli-1, Erg, and Elf-1 acting on the promoter and a -8-kb enhancer.
Angiogenesis is critical to the growth and regeneration of tissue but is also a key component of tumor growth and chronic inflammatory disorders. Endoglin plays a key role in angiogenesis by modulating cellular responses to transforming growth factor-beta (TGF-beta) signaling and is upregulated in proliferating endothelial cells. To gain insights into the transcriptional hierarchies that govern endoglin expression, we used a combination of comparative genomic, biochemical, and transgenic approaches. Both the promoter and a region 8 kb upstream of exon 1 were active in transfection assays in endothelial cells. In transgenic mice, the promoter directed low-level expression to a subset of endothelial cells. By contrast, inclusion of the -8 enhancer resulted in robust endothelial activity with additional staining in developing ear mesenchyme. Subsequent molecular analysis demonstrated that both the -8 enhancer and the promoter depend on conserved Ets sites, which were bound in endothelial cells in vivo by Fli-1, Erg, and Elf-1. This study therefore establishes the transcriptional framework within which endoglin functions during angiogenesis.
Department of Hematology, Cambridge Institute of Medical Research, University of Cambridge, Cambridge CB2 2XY, UK.
John E
JE
Pimanda
W Y Iris
WY
Chan
Ian J
IJ
Donaldson
Mark
M
Bowen
Anthony R
AR
Green
Berthold
B
Göttgens
D000818:Animals; D004285:Dogs; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D036383:Ephrin-A2 / Q000235:genetics / Q000378:metabolism*; D005091:Exons / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000502:physiology; D009893:Opossums; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D000071063:Endoglin; C502004:Eng protein, mouse; D036383:Ephrin-A2; C497426:Fli1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051789:Proto-Oncogene Protein c-fli-1; D016212:Transforming Growth Factor beta