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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3153-3160.
Prepublished online as a Blood First Edition Paper on December 13, 2005; DOI 10.1182/blood-2005-08-3206.
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Submitted August 11, 2005
Accepted November 30, 2005
Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis
Xuling Huang, Courtney Brown, Weihua Ni, Elizabeth Maynard, Alan C Rigby, and Peter Oettgen*
Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Medicine, and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, MA, USA
Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Division of Molecular and Vascular Medicine, Harvard Institutes of Medicine, Boston, MA, USA; Department of Medicine, and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, MA, USA
Division of Molecular and Vascular Medicine, Harvard Institutes of Medicine, Boston, MA, USA
* Corresponding author; email: joettgen{at}bidmc.harvard.edu.
The Ets transcription factors regulate a wide variety of biological processes. Several members have been shown to play a role in regulating angiogenesis and vascular development. For example, the Ets factor ELF-1, is enriched in the developing vasculature of the embryo, where it regulates the expression of the Tie2 gene. We have determined that ELF-1 and Tie2 expression are also enriched in tumor blood vessels, and have identified a short peptide, 34 amino acids in length, corresponding to the terminal portion of the highly conserved ETS domain, that potently blocks the function of ELF-1. A tailored ELF-1 blocking peptide, containing a 12 amino acid HIV-1 TAT protein, readily crosses the cell membrane and enters into the nucleus of endothelial cells, leading to a marked reduction in the expression of ELF-1 gene targets in endothelial cells including Tie2 and endothelial nitric oxide synthase. Furthermore, the ELF-1 blocking peptide potently inhibits Angiopoietin-1 mediated endothelial cell migration. Systemic administration of this peptide markedly attenuates B16 melanoma tumor growth and tumor associated angiogenesis in nude mice. These results support the function of ELF-1 in the regulation of Tie2 gene expression during the development of tumor angiogenesis.
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