RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis

Zhang, Duanwu; Shao, Jing; Lin, Juan; Zhang, Na; Lu, Bao; Lin, Sheng; Dong, Meng; Han, Jiahuai

doi:10.1126/science.1172308

Cited by 1,673 publications

(1,724 citation statements)

References 24 publications

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“…However, it remains unclear whether MAPKs regulate autophagy in inflammation-associated tumorigenesis. The latest advances in cell death have revealed that the RIP1 and RIP3 kinases are essential components of a signaling pathway that mediates caspase-independent cell death (necrosis) (Cho et al, 2009;Degterev et al, 2008;He et al, 2009;Zhang et al, 2009). RIPs are well-characterized kinases that transmit TNFα signaling and induce the activation of MAPKs.…”

Section: Perspectivesmentioning

confidence: 99%

MAPK signaling in inflammation-associated cancer development

2010

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Mitogen-activated protein (MAP) kinases comprise a family of protein-serine/threonine kinases, which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms, including mammals. These kinases, including ERKs, JNKs and p38s, are regulated by a phosphorelay cascade, with a prototype of three protein kinases that sequentially phosphorylate one another. MAPKs transduce extracellular signals into a variety of cellular processes, such as cell proliferation, survival, death, and differentiation. Consistent with their essential cellular functions, MAPKs have been shown to play critical roles in embryonic development, adult tissue homeostasis and various pathologies. In this review, we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and, particularly, inflammation-associated cancer development.

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Section: Perspectivesmentioning

confidence: 99%

MAPK signaling in inflammation-associated cancer development

2010

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“…When excessive, however, it may impair the epithelial barrier, leading to severe gut pathology 12, 13. Unlike apoptosis, necrosis is described as an uncontrolled and accidental form of cell death until genetically determined, regulated processes that mediates necrotic cellular demise, which were recently identified and are now termed programmed necrosis or necroptosis 14, 15. Necroptosis shares with necrosis the fact that dying cells display the morphological features of necrosis but not of apoptosis, but is highly regulated by an intracellular protein platform 14, 16.…”

Section: Introductionmentioning

confidence: 99%

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Wen

Ling

Yang

et al. 2016

J Cellular Molecular Medi

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Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor‐interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain‐like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin‐1. In addition, the combined treatment of necrostatin‐1 and the pan‐caspase inhibitor Z‐VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin‐1 pre‐treatment reduced the necroptotic death of oxygen‐glucose deprivation challenged intestinal epithelial cell‐6 cells, which in turn dampened the production of pro‐inflammatory cytokines (tumour necrosis factor‐α and interleukin‐1β), and suppressed high‐mobility group box‐1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll‐like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3‐dependent necroptosis pathway in intestinal I/R‐induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.

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“…This hybrid form of cell death occurs upon cytokine-mediated death receptor activation, in the setting of caspase inhibition and seems to be under the control of the adaptor proteins receptor-interacting protein (RIP)1 and RIP3 kinase and prominently involves reactive oxygen species (ROS) (Kim et al, 2007;Zhang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Necrostatin Decreases Oxidative Damage, Inflammation, and Injury after Neonatal HI

Northington

Chavez‐Valdez

Graham

et al. 2010

J Cereb Blood Flow Metab

188

194

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Necrostatin-1 inhibits receptor-interacting protein (RIP)-1 kinase and programmed necrosis and is neuroprotective in adult rodent models. Owing to the prominence of necrosis and continuum cell death in neonatal hypoxia-ischemia (HI), we tested whether necrostatin was neuroprotective in the developing brain. Postnatal day (P)7 mice were exposed to HI and injected intracerebroventricularly with 0.1 lL of 80 lmol necrostatin, Nec-1, 5-(1H-Indol-3-ylmethyl)-(2-thio-3-methyl) hydantoin, or vehicle. Necrostatin significantly decreased injury in the forebrain and thalamus at P11 and P28. There was specific neuroprotection in necrostatin-treated males. Necrostatin treatment decreased necrotic cell death and increased apoptotic cell death. Hypoxia-ischemia enforced RIP1-RIP3 complex formation and inhibited RIP3-FADD (Fas-associated protein with death domain) interaction, and these effects were blocked by necrostatin. Necrostatin also decreased HI-induced oxidative damage to proteins and attenuated markers of inflammation coincidental with decreased nuclear factor-jB and caspase 1 activation, and FLIP ((Fas-associated death-domain-like IL-1b-converting enzyme)-inhibitory protein) gene and protein expression. In this model of severe neonatal brain injury, we find that cellular necrosis can be managed therapeutically by a single dose of necrostatin, administered after HI, possibly by interrupting RIP1-RIP3-driven oxidative injury and inflammation. The effects of necrostatin treatment after HI reflect the importance of necrosis in the delayed phases of neonatal brain injury and represent a new direction for therapy of neonatal HI.

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RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis

Cited by 1,673 publications

References 24 publications

MAPK signaling in inflammation-associated cancer development

MAPK signaling in inflammation-associated cancer development

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Necrostatin Decreases Oxidative Damage, Inflammation, and Injury after Neonatal HI

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