Hypoxia-specific downregulation of endogenous human VEGF-A gene by hypoxia-driven expression of artificial transcription factor.
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.
Mori
Tomoaki
T
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo-ku, Kyoto, 615-8510, Japan.
Sasaki
Jun
J
Aoyama
Yasuhiro
Y
Sera
Takashi
T
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
D012097:Repressor Proteins; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
Adv Drug Deliv Rev. 2009 Jul 2;61(7-8):513-26
19394375
Biochem Biophys Res Commun. 2009 Dec 18;390(3):845-8
19836352
J Biol Chem. 1996 Feb 16;271(7):3877-83
8632007
Gene Ther. 2000 Mar;7(6):493-8
10757022
Cancer Res. 1999 Jan 1;59(1):99-106
9892193
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15225-30
15475575
Nat Med. 1998 Mar;4(3):336-40
9500609
Biochemistry. 1994 Aug 30;33(34):10450-6
7520755
Nucleic Acids Res. 2005 Apr 28;33(8):e74
15860771
Circ Res. 1995 Sep;77(3):638-43
7641334
Nature. 1993 Apr 29;362(6423):841-4
7683111
Nat Rev Cancer. 2008 Aug;8(8):579-91
18596824
Nat Med. 2002 Dec;8(12):1427-32
12415262
Anticancer Agents Med Chem. 2007 Mar;7(2):223-45
17348829
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9480-5
12084814
J Mol Med (Berl). 1999 Jul;77(7):527-43
10494799
Mol Ther. 2008 Jun;16(6):1033-40
18398429
Biochemistry. 2002 Jun 4;41(22):7074-81
12033941
Dev Biol. 2003 Dec 15;264(2):443-55
14651929
Nat Rev Drug Discov. 2006 Feb;5(2):123-32
16518379
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11393-8
12177445
Proc Natl Acad Sci U S A. 1994 May 10;91(10):4509-13
8183939
J Biol Chem. 1991 Jun 25;266(18):11947-54
1711045
Cancer Res. 2003 Dec 15;63(24):8968-76
14695215
J Biol Chem. 2001 Apr 6;276(14):11323-34
11145970
J Virol. 2006 Jun;80(11):5405-12
16699021