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10.1074/jbc.RA118.002911

http://scihub22266oqcxt.onion/10.1074/jbc.RA118.002911
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suck abstract from ncbi


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pmid29794136
      J+Biol+Chem 2018 ; 293 (28 ): 11109-11118
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  • The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells #MMPMID29794136
  • AlAbdi L ; He M ; Yang Q ; Norvil AB ; Gowher H
  • J Biol Chem 2018[Jul]; 293 (28 ): 11109-11118 PMID29794136 show ga
  • Formation of the vasculature by angiogenesis is critical for proper development, but angiogenesis also contributes to the pathogenesis of various disorders, including cancer and cardiovascular diseases. Vascular endothelial zinc finger 1 (Vezf1), is a Krüppel-like zinc finger protein that plays a vital role in vascular development. However, the mechanism by which Vezf1 regulates this process is not fully understood. Here, we show that Vezf1(-/-) mouse embryonic stem cells (ESC) have significantly increased expression of a stem cell factor, Cbp/p300-interacting transactivator 2 (Cited2). Compared with WT ESCs, Vezf1(-/-) ESCs inefficiently differentiated into endothelial cells (ECs), which exhibited defects in the tube-formation assay. These defects were due to reduced activation of EC-specific genes concomitant with lower enrichment of histone 3 acetylation at Lys(27) (H3K27) at their promoters. We hypothesized that overexpression of Cited2 in Vezf1(-/-) cells sequesters P300/CBP away from the promoters of proangiogenic genes and thereby contributes to defective angiogenesis in these cells. This idea was supported by the observation that shRNA-mediated depletion of Cited2 significantly reduces the angiogenic defects in the Vezf1(-/-) ECs. In contrast to previous studies that have focused on the role of Vezf1 as a transcriptional activator of proangiogenic genes, our findings have revealed a role for Vezf1 in modulating the expression of the antiangiogenic factor Cited2. Vezf1 previously has been characterized as an insulator protein, and our results now provide insights into the mechanism, indicating that Vezf1 can block inappropriate, nonspecific interactions of promoters with cis-located enhancers, preventing aberrant promoter activation.
  • |*Cell Differentiation [MESH]
  • |*Gene Expression Regulation [MESH]
  • |Angiogenesis Inhibitors/genetics/*metabolism [MESH]
  • |Animals [MESH]
  • |Cells, Cultured [MESH]
  • |DNA-Binding Proteins [MESH]
  • |Embryonic Stem Cells/cytology/*metabolism [MESH]
  • |Endothelium, Vascular/cytology/*metabolism [MESH]
  • |Kruppel-Like Transcription Factors/*physiology [MESH]
  • |Mice [MESH]
  • |Mice, Knockout [MESH]
  • |Promoter Regions, Genetic [MESH]
  • |Repressor Proteins/*physiology [MESH]
  • |Trans-Activators/*physiology [MESH]


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