title: Hypoxia-specific downregulation of endogenous human VEGF-A gene by hypoxia-driven expression of artificial transcription factor.
abstract: Repression of vascular endothelial growth factor A (VEGF-A) is an attractive approach to cancer therapy. Although zinc-finger-based artificial transcription factors (ATFs) were constructed for human VEGF-A and constitutive expressions of ATFs were previously shown to downregulate the endogenous VEGF-A gene expression, repression of VEGF-A specifically in hypoxic tumors is desirable for therapeutic application of ATF technology. Here, we describe hypoxia-driven expression of the ATF for hypoxia-specific repression of human VEGF-A gene. We constructed a hypoxia-driven promoter for the ATF expression and placed it upstream of the ATF-encoding region. The resulting hypoxia-driven expression plasmids induced the expression of ATFs specifically in hypoxia, and the hypoxia-specific expression of ATFs effectively downregulated the VEGF-A expression in hypoxia, but not in normoxia. Thus, the engineered expression system of ATFs may enable repression of VEGF-A expression specifically in hypoxic tumors without affecting normal, healthy tissues.
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo-ku, Kyoto, 615-8510, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Mori
authors.forename: Jun
authors.initials: J
authors.lastname: Sasaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Aoyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Sera
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D012097:Repressor Proteins; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
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