RRC ID 48813
著者 Sakaue T, Sakakibara I, Uesugi T, Fujisaki A, Nakashiro KI, Hamakawa H, Kubota E, Joh T, Imai Y, Izutani H, Higashiyama S.
タイトル The CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells.
ジャーナル Sci Rep
Abstract Vascular endothelial cell growth factor receptor 2 (VEGFR2) is an essential receptor for the homeostasis of endothelial cells. In this study, we showed that NEDD8-conjugated Cullin3 (CUL3)-based ubiquitin E3 (UbE3) ligase plays a crucial role in VEGFR2 mRNA expression. Human umbilical vein endothelial cells treated with MLN4924, an inhibitor of NEDD8-activating enzyme, or with CUL3 siRNA drastically lost their response to VEGF due to the intense decrease in VEGFR2 expression. Moreover, speckle-type POZ protein (SPOP) and death-domain associated protein (DAXX) were involved in the CUL3 UbE3 ligase complex as a substrate adaptor and a substrate, respectively. Knockdown of SPOP and CUL3 led to the upregulation of DAXX protein and downregulation of VEGFR2 levels. These levels were inversely correlated with one another. In addition, simultaneous knockdown of SPOP and DAXX completely reversed the downregulation of VEGFR2 levels. Moreover, the CUL3-SPOP-DAXX axis had the same effects on NOTCH1, DLL4 and NRP1 expression. Taken together, these findings suggest that the CUL3-SPOP-DAXX axis plays a very important role in endothelial cell function by targeting key angiogenic regulators.
巻・号 7
ページ 42845
公開日 2017-2-20
DOI 10.1038/srep42845
PII srep42845
PMID 28216678
PMC PMC5317005
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Co-Repressor Proteins Cullin Proteins / genetics Cullin Proteins / metabolism* Cyclopentanes / pharmacology Endothelial Cells / cytology Endothelial Cells / drug effects Endothelial Cells / metabolism* Gene Expression Regulation / drug effects Gene Knockdown Techniques Human Umbilical Vein Endothelial Cells Humans Molecular Chaperones Nuclear Proteins / genetics Nuclear Proteins / metabolism* Pyrimidines / pharmacology Repressor Proteins / genetics Repressor Proteins / metabolism* Signal Transduction / drug effects Vascular Endothelial Growth Factor Receptor-2 / genetics* Vascular Endothelial Growth Factor Receptor-2 / metabolism
IF 3.998
引用数 15
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
遺伝子材料 CSII-CMV-MCS-IRES2-Bsd (RDB04385)