Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis.
The Ets transcription factors regulate a wide variety of biologic 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 is 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 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.
Huang
Xuling
X
Beth Israel Deaconess Medical Center, Division of Cardiology, Department of Medicine, Boston, MA, USA.
Brown
Courtney
C
Ni
Weihua
W
Maynard
Elizabeth
E
Rigby
Alan C
AC
Oettgen
Peter
P
D042702:Angiopoietin-2 / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D036383:Ephrin-A2 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism* / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000096:biosynthesis / Q000235:genetics
D042702:Angiopoietin-2; D036383:Ephrin-A2; D050783:Proto-Oncogene Proteins c-ets; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D042787:Receptor, TIE-2