The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice.
Down syndrome critical region gene 1 (DSCR-1) short variant (DSCR-1s) is an inhibitor of calcineurin/NFAT signaling encoded by exons 4-7 of DSCR1. We previously reported that VEGF induces DSCR-1s expression in endothelial cells, which in turn negatively feeds back to attenuate endothelial cell activation. Here, in order to characterize the role of the promoter that drives DSCR-1s expression in mediating inducible expression in vivo and to determine the functional relevance of DSCR-1s in inflammation, we targeted a DNA construct containing 1.7 kb of the human DSCR1s promoter coupled to the lacZ reporter to the hypoxanthine guanine phosphoribosyl transferase (Hprt) locus of mice. We determined that lacZ was uniformly expressed in the endothelium of transgenic embryos but was markedly downregulated postnatally. Systemic administration of VEGF or LPS in adult mice resulted in cyclosporine A-sensitive reactivation of the DSCR1s promoter and endogenous gene expression in a subset of organs, including the heart and brain. The DSCR1s promoter was similarly induced in the endothelium of tumor xenografts. In a mouse model of endotoxemia, DSCR-1s-deficient mice demonstrated increased sepsis mortality, whereas adenovirus-mediated DSCR-1s overexpression protected against LPS-induced lethality. Collectively, these data suggest that the DSCR1s promoter directs vascular bed-specific expression in activated endothelium and that DSCR-1s serves to dampen the host response to infection.
Minami
Takashi
T
Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan. minami@med.rcast.u-tokyo.ac.jp
Yano
Kiichiro
K
Miura
Mai
M
Kobayashi
Mika
M
Suehiro
Jun-ichi
J
Reid
Patrick C
PC
Hamakubo
Takao
T
Ryeom
Sandra
S
Aird
William C
WC
Kodama
Tatsuhiko
T
D000367:Age Factors; D000818:Animals; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D050989:GATA2 Transcription Factor / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology; D050778:NFATC Transcription Factors / Q000502:physiology; D011401:Promoter Regions, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D042461:Vascular Endothelial Growth Factor A