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Identification of RIP1 kinase as a specific cellular target of necrostatins
Alternative TitleR1P1 激酶是NECROSTATINS抑制剂的特殊细胞靶点的鉴定证明
Alexei Degterev; Junichi Hitomi; Megan Germscheid; Irene L Ch'en; Olga Korkina; Xin Teng; Derek Abbott; Gregory D. Cuny; Yuan CY(袁承业); Gerhard Wagner; Stephen M. Hedrick; Scott A. Gerber; Alexey Lugovskoy; Yuan JY(袁钧瑛)
Source PublicationNat. Chem. Biol.
AbstractNecroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.
Subject Area生命有机化学
DepartmentTufts Univ; Harvard Univ; Univ Calif San Diego; Harvard Univ; Brigham & Womens Hosp; Beth Israel Deaconess Med Ctr; 上海有机所; Norris Cotton Canc Ctr; Dartmouth Med Sch
Indexed BySCI
WOS IDWOS:000255170400012
Citation statistics
Cited Times:988[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
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GB/T 7714
Alexei Degterev,Junichi Hitomi,Megan Germscheid,et al. Identification of RIP1 kinase as a specific cellular target of necrostatins[J]. Nat. Chem. Biol.,2008,4(5):313-321.
APA Alexei Degterev.,Junichi Hitomi.,Megan Germscheid.,Irene L Ch'en.,Olga Korkina.,...&袁钧瑛.(2008).Identification of RIP1 kinase as a specific cellular target of necrostatins.Nat. Chem. Biol.,4(5),313-321.
MLA Alexei Degterev,et al."Identification of RIP1 kinase as a specific cellular target of necrostatins".Nat. Chem. Biol. 4.5(2008):313-321.
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