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

다국어 초록 (Multilingual Abstract)

<P>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 <I>Flk-1</I>, 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 <I>Flk-1</I> transcription in both endothelium-differentiated mESCs and human umbilical vein endothelial cells (HUVECs). <I>In vitro</I> DNA binding assay showed direct interaction of CXXC5 on the <I>Flk-1</I> promoter region, and mutation on its DNA-binding motif abolished transcriptional activity. We showed that bone morphorgeneic protein 4 (BMP4) induced <I>CXXC5</I> transcription in the cells, and inhibitors of BMP signaling suppressed the <I>CXXC5</I> induction and the consequent <I>Flk-1</I> induction by BMP4 treatment. <I>CXXC5</I> knockdown resulted in suppression of BMP4-induced stress fiber formation (56.8±1.3% decrease, <I>P</I><0.05) and migration (54.6±1.9% decrease, <I>P</I><0.05) in HUVECs. The <I>in vivo</I> 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, <I>P</I><0.05) in <I>cxxc5</I> morpholino-injected zebrafish embryos and by supression of BMP4-induced angigogensis in subcutaneously injected Matrigel plugs in <I>CXXC5</I><SUP>−/−</SUP> mice. Overall, CXXC5 is a transcriptional activator for <I>Flk-1</I>, 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 <I>Flk-1</I> and mediates bone morphogenic protein-induced endothelial cell differentiation and vessel formation.</P>