Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells.
We conducted a genome-wide analysis of genes that are regulated by vascular endothelial growth factor (VEGF) in endothelial cells and identified DSCR1 to be most significantly induced. Consistent with an antagonistic function on calcineurin (CnA) signaling, expression of DSCR1 in endothelial cells blocked dephosphorylation, nuclear translocation, and activity of nuclear factor of activated T cell (NFAT), a transcription factor involved in mediating CnA signaling. DSCR1 was not only induced by VEGF, but also by other compounds activating CnA signaling, suggesting a more general role for DSCR1 in activated endothelial cells. Transient expression of DSCR1 attenuated inflammatory marker genes such as tissue factor (TF), E-selectin, and Cox-2, identifying a previously unknown regulatory role for DSCR1 in activated endothelial cells. In contrast, knock-down of endogenous DSCR1 increased NFAT activity and stimulated expression of inflammatory genes on activated endothelial cells. Thus, the negative regulatory feedback loop between DSCR1 and CnA signaling in endothelial cells identified may represent a potential molecular mechanism underlying the frequently transient expression of inflammatory genes following activation of endothelial cells.
Hesser
Boris A
BA
Department of Molecular Oncology, Genentech, South San Francisco, CA 94080, USA.
Liang
Xiao Huan
XH
Camenisch
Gieri
G
Yang
Suya
S
Lewin
David A
DA
Scheller
Richard
R
Ferrara
Napoleone
N
Gerber
Hans-Peter
HP
D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D018390:Gene Targeting; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000235:genetics* / Q000502:physiology
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D019040:E-Selectin; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C108612:RCAN1 protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D042442:Vascular Endothelial Growth Factors; D018799:Intercellular Adhesion Molecule-1; D013925:Thromboplastin; D019703:Calcineurin