FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP

Tsuchiya, Yosuke; Nakabayashi, Osamu; Nakano, Hiroyasu

doi:10.3390/ijms161226232

Cited by 139 publications

(115 citation statements)

References 137 publications

(154 reference statements)

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“…TNF-α signaling pathway is an important death receptor-mediated extrinsic apoptosis pathway [28], which exerts both anti-apoptotic and pro-apoptotic effects [29]. After binding to TNF-R1, on one hand, TNF-α activates NF-κB pathway and inhibits apoptosis; on the other hand, when NF-κB pathway is inactivated, it stimulates FADD and caspase 8 and promotes apoptosis [29].…”

Section: Discussionmentioning

confidence: 99%

Indole-3-Carbinol Induces Apoptosis of Hepatic Stellate Cells through K63 De-Ubiquitination of RIP1 in Rats

Zhu

et al. 2017

Cell Physiol Biochem

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Background/Aims: The apoptosis of activated hepatic stellate cells (HSCs) is the central event in the reversal of liver fibrosis. K63 de-ubiquitinated receptor-interacting protein (RIP)1 promotes apoptosis in tumor necrosis factor (TNF)-α signaling pathway. In the previous study, we have proved that indole-3-carbinol (I3C) could reverse different models of liver fibrosis in rats, but the mechanism is still unclear. Thus, the present research aimed to demonstrate the induction of I3C on apoptosis of HSCs and the underlying molecular mechanism. Methods: HSC-T6, an immortalized rat liver stellate cell line, was treated for 24 hours with 25, 50 and 100 µM of I3C. The apoptosis of HSC-T6 was analyzed by flow cytometric analysis, acridine orange staining and RT-PCR, respectively. K63 de-ubiquitination of RIP1 and the expression of ubiquitin ligases and deubiquitinases were analyzed by Co-IP assay and western blot. Knockdown of deubiquitinases was undertaken by small interfering RNA (siRNA). Results: The results of flow cytometric analysis indicated that the apoptotic rate of HSC-T6 was induced by I3C in a dose-dependent manner. Observation by acridine orange staining exhibited nuclear condensation and apoptotic bodies in I3C treated cells. Consistently, the expression ratio of Bax/bcl-2 was markedly increased by I3C. These results indicated that I3C could significantly induce apoptosis of HSC-T6 cells. Furthermore, Co-IP assay revealed K63 de-ubiquitination of RIP1 by I3C, associated with the induction of caspase 8. Although I3C had no effect on the expression of ubiquitin ligases cellular inhibitor of apoptosis 1/2 (cIAP1/2), the protein level of deubiquitinase cylindromatosis (CYLD) was significantly induced by I3C. Moreover, CYLD silencing reversed the pro-apoptosis induction effect of I3C and reduced the expression ratio of Bax/bcl-2 in HSC-T6 cells. Conclusion: These results demonstrated that I3C could induce apoptosis of HSC through RIP1 K63 de-ubiquitination by upregulating deubiquitinase CYLD.

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Section: Discussionmentioning

confidence: 99%

Indole-3-Carbinol Induces Apoptosis of Hepatic Stellate Cells through K63 De-Ubiquitination of RIP1 in Rats

Zhu

et al. 2017

Cell Physiol Biochem

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“…Accordingly, under NF-κB transcriptionally active conditions, cFLIP levels are high and the transient formation of complex II is inhibited. In contrast, when NF-κB activity is repressed and cFLIP levels low, Caspase-8 is activated and the cells succumb by apoptosis [40]. In line with a role for RIPK1 in NF-κB activation, RIPK1 deficient cells succumb by apoptosis upon single TNF stimulation [25, 41–43].…”

Section: The Late Nf-κb-dependent Cell Death Checkpointmentioning

confidence: 99%

More to Life than NF-κB in TNFR1 Signaling

Ting

Bertrand

2016

Trends in Immunology

219

207

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TNF is a master pro-inflammatory cytokine whose pathogenic role in inflammatory disorders has long been attributed to induction of pro-inflammatory mediators. TNF also activates cell survival and death pathways, and recent studies demonstrated that TNF also causes inflammation by inducing cell death. The default response of most cells to TNF is survival and NF-κB-mediated up-regulation of pro-survival molecules is a well-documented protective mechanism downstream of TNFR1. Recent studies revealed existence of an NF-κB-independent cell death checkpoint that restricts cell demise by inactivating RIPK1. Disruption of this checkpoint leads to RIPK1 kinase-dependent death and causes inflammation in vivo. These revelations bring complexity to the control of TNF-induced cell death, and suggest clinical benefit of RIPK1 inhibitors in TNF-driven human inflammatory disorders.

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“…Apoptosis, also known as type I programmed cell death, is characterized by chromosomal concentration, cell shrinkage, DNA degradation and apoptotic body formation, and needs the participation of caspases [92,93]. Although IVD cell loss due to apoptosis continues to occur throughout life, excessive apoptosis of IVD cell has been considered as an important cause of disc degeneration [94][95][96][97].…”

Section: Autophagy Protects Against Disc Degenerationmentioning

confidence: 99%