title: FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP.
abstract: cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS, and cFLIPR). cFLIP controls not only the classical death receptor-mediated extrinsic apoptosis pathway, but also the non-conventional pattern recognition receptor-dependent apoptotic pathway. In addition, cFLIP regulates the formation of the death receptor-independent apoptotic platform named the ripoptosome. Moreover, recent studies have revealed that cFLIP is also involved in a non-apoptotic cell death pathway known as programmed necrosis or necroptosis. These functions of cFLIP are strictly controlled in an isoform-, concentration- and tissue-specific manner, and the ubiquitin-proteasome system plays an important role in regulating the stability of cFLIP. In this review, we summarize the current scientific findings from biochemical analyses, cell biological studies, mathematical modeling, and gene-manipulated mice models to illustrate the critical role of cFLIP as a switch to determine the destiny of cells among survival, apoptosis, and necroptosis.
authors.affiliation: Department of Biochemistry, Toho University School of Medicine, Tokyo 143-8540, Japan. tsuchiya@med.toho-u.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Department of Biochemistry, Toho University School of Medicine, Tokyo 143-8540, Japan. necozame@med.toho-u.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakabayashi
authors.affiliation: Department of Biochemistry, Toho University School of Medicine, Tokyo 143-8540, Japan. hiroyasu.nakano@med.toho-u.ac.jp.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D009336:Necrosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: TNF-α; apoptosis; cFLIP; caspase-8; necroptosis; ubiquitin-proteasome system