Hypoxia-responsive element-mediated soluble Tie2 vector exhibits an anti-angiogenic activity in vitro under hypoxic condition.
Hypoxia-inducible factor-1 (HIF-1) is one of the key mammalian transcription factors and shows increased levels in both protein stability and intrinsic transcriptional activity during low oxygen tension. Hypoxia-activated functional HIF-1 protein binds to hypoxia-responsive elements (HRE) in the enhancers of several genes including VEGF, the major player in angiogenesis, and initiates their mRNA expression. The molecular mechanisms regulating the gene expression under hypoxic conditions could increase the therapeutic window of tumor-specific delivery systems. In this study, to examine hypoxia-specific production of anti-angiogenic therapeutic gene, we constructed 5 copies of HRE (5xHRE) of human VEGF linked to soluble Tie2 (sTie2) driven by minimal SV40 promoter (5xHRE/SV40/sTie2). Our data showed that under hypoxia the secreted sTie2 selectively inhibited tube formation and migration capacities of endothelial cells in vitro. Hence, we propose that the vector system, 5xHRE/SV40/sTie2, might be a useful tool for down-regulating tumor angiogenesis under hypoxic condition.
Jeong
Chul-Ho
CH
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Lee
You Mie
YM
Choi
Kyu-Sil
KS
Seong
Young Rim
YR
Kim
Yung-Jin
YJ
Im
Dong-Soo
DS
Kim
Kyu-Won
KW
D000803:Angiotensin I / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001483:Base Sequence; D001681:Biological Assay; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000628:therapy*; D009687:Nuclear Proteins / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000235:genetics* / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology; D020218:Response Elements / Q000235:genetics*; D013539:Simian virus 40 / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014470:Umbilical Cord / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
C497396:ARNT protein, human; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D000803:Angiotensin I; D042787:Receptor, TIE-2