ナカノ　ヒロヤス   Nakano Hiroyasu   中野　裕康    所属   東邦大学  医学部 医学科    東邦大学  医学部 医学科    職種   教授
言語種別	日本語
発表タイトル	Short form FLICE-inhibitory protein promotes TNFα-induced necroptosis in fibroblasts derived from CFLARs transgenic mice
会議名	細胞競合・ダイイングコード合同若手ワークショップ
主催者	新学術領域　細胞競合・ダイイングコード
発表形式	ポスター掲示
講演区分	一般
発表者・共同発表者	◎進藤綾大、山崎創、大村谷昌樹、荒木喜美、中野裕康
発表年月日	2017/01/17
開催地 （都市, 国名）	大阪府大阪市ホテルコスモスクエア国際交流センター
概要	Cellular FLICE-inhibitory protein (cFLIP) is a catalytically inactive homolog of the initiator caspase, caspase 8 and blocks apoptosis through binding to caspase 8. Human CFLAR gene encodes two proteins, a long form cFLIP (cFLIPL) and a short form cFLIP (cFLIPs) due to an alternative splicing. Recent studies have shown that expression of cFLIPs, but not cFLIPL promotes programmed necrosis (also referred to as necroptosis) in an immortalized human keratinocyte cell line, HaCaT. Here, we found that expression of cFLIPs similarly promoted necroptosis in immortalized fibroblasts. To further expand this observation and exclude the possibility that immortalization process of keratinocytes or fibroblasts might affect the phenotype induced by cFLIPs expression, we generated human CFLARs transgenic (Tg) mice. Primary fibroblasts derived from CFLARs Tg mice were increased in susceptibility to TNFα-induced necroptosis, but not apoptosis compared to wild-type (WT) fibroblasts. Moreover, hallmarks of necroptosis, such as phosphorylation of receptor-interacting protein kinase (RIPK)1 and RIPK3, and oligomer formation of mixed lineage kinase domain-like (MLKL) were robustly induced in CFLARs Tg fibroblasts compared to wild-type fibroblasts following TNFα stimulation. Thus, cFLIPs-dependent promotion of necroptosis is not unique to immortalized keratinocytes or fibroblasts, but also to generalized to primary fibroblasts.