Transcription enhancer factor 3 (TEF3) mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1L) in endothelial cells.
The Down syndrome candidate region 1 gene (DSCR1) can be expressed as four isoforms, one of which is the well-studied isoform 4 (DSCR1-4) that is induced by VEGF-A(165) to provide a negative feedback loop in the VEGF-A(165)-induced angiogenesis. We reported previously that another DSCR1 isoform, DSCR1-1L, was also up-regulated by VEGF-A(165) in cultured endothelial cells and in several in vivo models of pathological angiogenesis and that different from DSCR1-4, DSCR1-1L overexpression alone induced cultured endothelial cell proliferation and promoted angiogenesis in Matrigel assays. It was reported recently that tumor growth was greatly repressed in DSCR1 knock-out mice. Although DSCR1-4 transcription was primarily regulated by NFAT, the mechanism regulating DSCR1-1L expression was still unknown. We developed human DSCR1-1L promoter-driven luciferase system and found that deletion of a putative conserved M-CAT site located 1426-bp upstream of the translation start site blunted promoter activity. We further showed that knockdown of TEF3, not other members of TEF family inhibited VEGF-A(165)-induced DSCR1-1L expression. We also demonstrated that TEF3 directly interacted with the putative M-CAT site in the DSCR1-1L promoter in vitro and in vivo. Finally, overexpression of TEF3 isoform 1, not isoform 3, in HUVEC was sufficient to induce DSCR1-1L expression even in the absence of VEGF-A(165) stimulation. Taken together, we elucidated a novel function of transcriptional factor TEF3. TEF3 was required for DSCR1-1L expression through binding to the M-CAT site in its promoter and could be an attractive target for anti-angiogenesis therapy.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Xin
X
Liu
Dezheng
D
Zhao
Liuliang
L
Qin
Jian
J
Li
Huiyan
H
Zeng
D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004314:Down Syndrome / Q000378:metabolism*; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007797:Laminin / Q000737:chemistry; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D011509:Proteoglycans / Q000737:chemistry; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; D004338:Drug Combinations; D007797:Laminin; D009124:Muscle Proteins; D020033:Protein Isoforms; D011509:Proteoglycans; C100360:RCAN2 protein, human; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; C059485:matrigel; D003094:Collagen