Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway.
Down syndrome candidate region 1 (DSCR1) is one of more than 50 genes located in a region of chromosome 21 that has been implicated in Down syndrome. DSCR1 can be expressed as four isoforms, one of which, isoform 4 (DSCR1-4), has recently been found to be strongly induced by vascular endothelial growth factor A (VEGF-A(165)) and to provide a negative feedback loop that inhibits VEGF-A(165)-induced endothelial cell proliferation in vitro and angiogenesis in vivo. We report here that another DSCR1 isoform, DSCR1-1L, is also up-regulated by VEGF-A(165) in cultured endothelial cells and is strongly expressed in several types of pathologic angiogenesis in vivo. In contrast to DSCR1-4, the overexpression of DSCR1-1L induced the proliferation and activation of the transcription factor NFAT in cultured endothelial cells and promoted angiogenesis in Matrigel assays in vivo, even in the absence of VEGF-A. Similarly, small interfering RNAs specific for DSCR1-1L and DSCR1-4 had opposing inhibitory and stimulatory effects, respectively, on these same functions. DSCR1-4 is thought to inhibit angiogenesis by inactivating calcineurin, thereby preventing activation and nuclear translocation of NFAT, a key transcription factor. In contrast, DSCR1-1L, regulated by a different promoter than DSCR1-4, activates NFAT and its proangiogenic activity is inhibited by cyclosporin, an inhibitor of calcineurin. In sum, DSCR1-1L, unlike DSCR1-4, potently activates angiogenesis and could be an attractive target for antiangiogenesis therapy.
Qin
Liuliang
L
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue RN 270A, Boston, MA 02215, USA.
Zhao
Dezheng
D
Liu
Xin
X
Nagy
Janice A
JA
Hoang
Mien Van
MV
Brown
Lawrence F
LF
Dvorak
Harold F
HF
Zeng
Huiyan
H
D021581:Active Transport, Cell Nucleus; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D007797:Laminin / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051379:Mice; D018832:Molecular Chaperones; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D011509:Proteoglycans / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; C110524:DSCR4 lncRNA, human; D004338:Drug Combinations; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C410584:PSMG1 protein, human; D010446:Peptide Fragments; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D011506:Proteins; D011509:Proteoglycans; C108612:RCAN1 protein, human; C100360:RCAN2 protein, human; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; C110162:VPS26C protein, human; D042461:Vascular Endothelial Growth Factor A; C511613:vascular endothelial growth factor A (138-165); C059485:matrigel; D003094:Collagen; D019703:Calcineurin