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
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Short form FLICE-inhibitory protein promotes TNFalpha-induced necroptosis in fibroblasts derived from CFLARs transgenic mice
掲載誌名	正式名：Biochem Biophys Res Commun ISSNコード：1090-2104
出版社	Elsevier
巻・号・頁	480(1),pp.23-28
著者・共著者	Shindo R, Yamazaki S, Ohmuraya M, Araki K, Nakano H.
担当区分	最終著者,責任著者
発行年月	2016/11
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 TNFalpha-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 TNFalpha stimulation. Thus, cFLIPs-dependent promotion of necroptosis is not unique to immortalized keratinocytes or fibroblasts, but also to generalized to primary fibroblasts.
DOI	10.1016/j.bbrc.2016.10.015