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

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)615-626
Number of pages12
JournalFASEB Journal
Volume28
Issue number2
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Endothelial cells
Cell Differentiation
Bone
Endothelial Cells
Bone and Bones
Human Umbilical Vein Endothelial Cells
Transcription
Proteins
Stem cells
Activating Transcription Factor 1
Activating Transcription Factors
Morpholinos
Stress Fibers
Nucleotide Motifs
Vascular Endothelial Growth Factor Receptor
DNA
Zinc Fingers
Zebrafish
Genetic Promoter Regions
Endothelium

Keywords

  • Caudal vein plex vessel formation
  • HUVECs
  • Mouse embryonic stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation. / Kim, Hyun Yi; Yang, Dong Hwa; Shin, Song Weon; Kim, Mi Yeon; Yoon, Jae Hyun; Kim, Suhyun; Park, Hae Chul; Kang, Dong Woo; Min, Dosik; Hur, Man Wook; Choi, Kang Yell.

In: FASEB Journal, Vol. 28, No. 2, 01.01.2014, p. 615-626.

Research output: Contribution to journalArticle

Kim, Hyun Yi ; Yang, Dong Hwa ; Shin, Song Weon ; Kim, Mi Yeon ; Yoon, Jae Hyun ; Kim, Suhyun ; Park, Hae Chul ; Kang, Dong Woo ; Min, Dosik ; Hur, Man Wook ; Choi, Kang Yell. / CXXC5 is a transcriptional activator of Flk-1 and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation. In: FASEB Journal. 2014 ; Vol. 28, No. 2. pp. 615-626.
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AU - Kim, Mi Yeon

AU - Yoon, Jae Hyun

AU - Kim, Suhyun

AU - Park, Hae Chul

AU - Kang, Dong Woo

AU - Min, Dosik

AU - Hur, Man Wook

AU - Choi, Kang Yell

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