CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation

Kim, H.Y., Yang, D.H., Shin, S.W., Kim, M.Y., Yoon, J.H., Kim, S., Park, H.C., Kang, D.W., Min, D., Hur, M.W., and Choi, K.Y.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology   28(2): 615-26 (Journal)
Registered Authors
Kim, Suhyun, Park, Hae-Chul
HUVECs, mouse embryonic stem cells, caudal vein plex vessel formation
MeSH Terms
  • Angiogenesis Inducing Agents/pharmacology
  • Animals
  • Bone Morphogenetic Protein 4/pharmacology*
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Cell Differentiation/drug effects
  • Cell Differentiation/genetics
  • Cell Differentiation/physiology*
  • Humans
  • Mice
  • Vascular Endothelial Growth Factor Receptor-2/genetics
  • Vascular Endothelial Growth Factor Receptor-2/metabolism*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
24136587 Full text @ FASEB J.

CXXC5 is a member of a small subset of proteins containing CXXC-type zinc-finger domain. Here, we show that CXXC5 is a transcription factor activating Flk-1, a receptor for vascular endothelial growth factor. CXXC5 and Flk-1 were accmulated in nucli and membrane of mouse embryonic stem cells (mESCs), respectively, during their endothelial differentiation. CXXC5 overexpression induced Flk-1 transcription in both endothelium-differentiated mESCs and human umbilical vein endothelial cells (HUVECs). In vitro DNA binding assay showed direct interaction of CXXC5 on the Flk-1 promoter region, and mutation on its DNA-binding motif abolished transcriptional activity. We showed that bone morphorgeneic protein 4 (BMP4) induced CXXC5 transcription in the cells, and inhibitors of BMP signaling suppressed the CXXC5 induction and the consequent Flk-1 induction by BMP4 treatment. CXXC5 knockdown resulted in suppression of BMP4-induced stress fiber formation (56.8±1.3% decrease, P<0.05) and migration (54.6±1.9% decrease, P<0.05) in HUVECs. The in vivo roles of CXXC5 in BMP-signaling-specific vascular development and angiogenesis were shown by specific defect of caudal vein plex vessel formation (57.9±11.8% decrease, P<0.05) in cxxc5 morpholino-injected zebrafish embryos and by supression of BMP4-induced angigogensis in subcutaneously injected Matrigel plugs in CXXC5/ mice. Overall, CXXC5 is a transcriptional activator for Flk-1, mediating BMP signaling for differentiation and migration of endothelial cell and vessel formation.

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