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To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in <jats:italic>RNF213<\/jats:italic> are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of <jats:italic>RNF213<\/jats:italic> both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of <jats:italic>RNF213<\/jats:italic>. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of <jats:italic>RNF213<\/jats:italic> in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.<\/jats:p>","DOI":"10.1038\/srep13191","type":"journal-article","created":{"date-parts":[[2015,8,17]],"date-time":"2015-08-17T11:12:41Z","timestamp":1439809961000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":147,"title":["Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells"],"prefix":"10.1038","volume":"5","author":[{"given":"Kazuhiro","family":"Ohkubo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunari","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirosuke","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Akamine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshito","family":"Ishizaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Matsushita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Sanefuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Torisu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Ihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Sardiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiro","family":"Hara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,8,17]]},"reference":[{"key":"BFsrep13191_CR1","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/archneur.1969.00480090076012","volume":"20","author":"J Suzuki","year":"1969","unstructured":"Suzuki, J. & Takaku, A. 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