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

 Hyun-Yi Kim  ;  Dong-Hwa Yang  ;  Song-Weon Shin  ;  Mi-Yeon Kim  ;  Jae-Hyun Yoon  ;  Suhyun Kim  ;  Hae-Chul Park  ;  Dong Woo Kang  ;  DoSik Min  ;  Man-Wook Hur  ;  Kang-Yell Choi 
 FASEB JOURNAL, Vol.28(2) : 615-626, 2014 
Journal Title
Issue Date
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*
HUVECs ; caudal vein plex vessel formation ; mouse embryonic stem cells
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.—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., Choi, K.-Y. CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Hur, Man Wook(허만욱) ORCID logo https://orcid.org/0000-0002-3416-1334
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