본문 바로가기
KERD
논문KCI 등재

LDB2 regulates the expression of DLL4 through the formation of oligomeric complexes in endothelial cells

0

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류화학

초록

Delta-like ligand 4 (DLL4) expression in endothelial cells is intimately associated with angiogenic sprouting and vascular remodeling, but the precise mechanism of transcriptional regulation of DLL4 remains incompletely understood. Here, we showed that LIM-domain binding protein 2 (LDB2) plays an important role in regulating basal DLL4 and VEGF-induced DLL4 expression. Knockdown of LDB2 using siRNA enhanced endothelial sprouting and tubular network formation in vitro. Injection of ldb2-morpholino resulted in defective development of intersegmental vessels in zebrafish. Reduction or overexpression of LDB2 in endothelial cells decreased or increased DLL4 expression. LDB2 regulated DLL4 promoter activity by binding to its promoter region and the same promoter region was occupied and regulated by the LMO2/TAL1/GATA2 complex. Interestingly, LDB2 also mediated VEGF-induced DLL4 expression in endothelial cells. The regulation of DLL4 by the LDB2 complex provides a novel mechanism of DLL4 transcriptional control that may be exploited to develop therapeutics for aberrant vascular remodeling.

Abstract

Delta-like ligand 4 (DLL4) expression in endothelial cells is intimately associated with angiogenic sprouting and vascular remodeling, but the precise mechanism of transcriptional regulation of DLL4 remains incompletely understood. Here, we showed that LIM-domain binding protein 2 (LDB2) plays an important role in regulating basal DLL4 and VEGF-induced DLL4 expression. Knockdown of LDB2 using siRNA enhanced endothelial sprouting and tubular network formation in vitro. Injection of ldb2-morpholino resulted in defective development of intersegmental vessels in zebrafish. Reduction or overexpression of LDB2 in endothelial cells decreased or increased DLL4 expression. LDB2 regulated DLL4 promoter activity by binding to its promoter region and the same promoter region was occupied and regulated by the LMO2/TAL1/GATA2 complex. Interestingly, LDB2 also mediated VEGF-induced DLL4 expression in endothelial cells. The regulation of DLL4 by the LDB2 complex provides a novel mechanism of DLL4 transcriptional control that may be exploited to develop therapeutics for aberrant vascular remodeling.

참고문헌 (30)

  1. Blanco R, "VEGF and Notch in tip and stalk cell selection", Cold Spring Harb Perspect Med, 3, pp.a006569~ (2013)
  2. Gridley T, "Notch signaling in the vasculature", Curr Top Dev Biol, 92, pp.277~309 (2010)
  3. Lobov IB, "Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting", Proc Natl Acad Sci U S A, 104, pp.3219~3224 (2007)[DOI]
  4. Suchting S, "The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching", Proc Natl Acad Sci U S A, 104, pp.3225~3230 (2007)[DOI]
  5. Gerhardt H, "VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia", J Cell Biol, 161, pp.1163~1177 (2003)[DOI]
  6. Hellstrom M, "Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis", Nature, 445, pp.776~780 (2007)[DOI]
  7. Agulnick AD, "Interactions of the LIM-domainbinding factor Ldb1 with LIM homeodomain proteins", Nature, 384, pp.270~272 (1996)[DOI]
  8. Becker T, "Multiple functions of LIM domain-binding CLIM", NLI, Mech Dev, pp.2002, 117[DOI]
  9. Matthews JM, "LIM-domain-binding protein 1: a multifunctional cofactor that interacts with diverse proteins", EMBO Rep, 4, pp.1132~1137 (2003)[DOI]
  10. Bach I, "A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins", Genes Dev, 11, pp.1370~1380 (1997)[DOI]
  11. Wadman IA, "The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1", NLI proteins, 1997, pp.16, 3145~3157
  12. Song SH, "Multiple functions of Ldb1 required for beta-globin activation during erythroid differentiation", Blood, 116, pp.2356~2364 (2010)[DOI]
  13. Bridge G, "The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis", Blood, 120, pp.5063~5072 (2012)[DOI]
  14. Mukhopadhyay M, "Functional ablation of the mouse Ldb1 gene results in severe patterning defects during gastrulation", Development, 130, pp.495~505 (2003)[DOI]
  15. Corada M, "The Wnt", beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4, Dev Cell, pp.2010, 18[DOI]
  16. Hayashi H, "Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells", PLoS One, 3, pp.e2401~ (2008)[DOI]
  17. Seo S, "The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development", Dev Biol, 294, pp.458~470 (2006)[DOI]
  18. Wythe JD, "ETS factors regulate Vegf-dependent arterial specification", Dev Cell, 26, pp.45~58 (2013)[DOI]
  19. Sacilotto N, "Analysis of Dll4 regulation reveals a combinatorial role for Sox and Notch in arterial development", Proc Natl Acad Sci U S A, 110, pp.11893~11898 (2013)[DOI]
  20. Patterson LJ, "Scl is required for dorsal aorta as well as blood formation in zebrafish embryos", Blood, 105, pp.3502~3511 (2005)[DOI]
  21. Visvader JE, "Unsuspected role for the T-cell leukemia protein SCL", tal-1 in vascular development, 1998, pp.12, 473~479
  22. Lazrak M, "The bHLH TAL-1", SCL regulates endothelial cell migration and morphogenesis, 2004, pp.117, 1161~1171
  23. Deleuze V, "TAL-1", SCL and its partners E47 and LMO2 up-regulate VE-cadherin expression in endothelial cells, 2007, pp.27, 2687~2697
  24. Yamada Y, "The oncogenic LIM-only transcription factor Lmo2 regulates angiogenesis but not vasculogenesis in mice", Proc Natl Acad Sci U S A, 97, pp.320~324 (2000)[DOI]
  25. Javerzat S, "Correlating global gene regulation to angiogenesis in the developing chick extra-embryonic vascular system", PLoS One, 4, pp.e7856~ (2009)[DOI]
  26. Min JK, "Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice", Blood, 109, pp.1495~1502 (2007)[DOI]
  27. Nakatsu MN, "An optimized three-dimensional in vitro model for the analysis of angiogenesis", Methods Enzymol, 443, pp.65~82 (2008)
  28. Choi HJ, "Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2", Nat Commun, 6, pp.6943~ (2015)[DOI]
  29. Han-Heom Na, "SETDB1 mediated FosB expression increases the cell proliferation rate during anticancer drug therapy", BMB Reports, 49(4), pp.238~243 (2016), 생화학분자생물학회
  30. 송인선, "GATA4 negatively regulates bone sialoprotein expression in osteoblasts", BMB Reports, 49(6), pp.343~348 (2016), 생화학분자생물학회

관련 논문AI추천

이 간행물의 다른 논문 (7건)