The B-RafV600E inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury

Jx, Li; Jm, Feng; Wang, Y; Xh, Li; Chen, XX; Y, Su; Shen, Yuntian; Chen, Y; Xiong, Bing; Ch, Yang; Ding, Jianxun; Zh, Miao

doi:10.1038/cddis.2014.241

Cited by 209 publications

(210 citation statements)

References 42 publications

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“…Supporting this idea, biopsies of liver from patients suffering drug-induced liver injury have higher levels of phosphorylated MLKL at the Ser358 28 and patients affected by toxic epidermal necrolysis, which present extensive keratinocyte death in the epidermis, 37 have increased levels of RIPK3 and phosphorylated MLKL. 38 Altogether, these findings suggest opportunities for RIPK3 inhibitors in the treatment of diseases where high RIPK3 kinase activity promotes human pathologies, also including steatohepatitis 36 and Gaucher's disease.…”

Section: Discussionmentioning

confidence: 62%

“…Few inhibitors for murine RIPK3 have been described: Dabrafenib, GSK'843 and GSK'872. 27,28 In order to identify a novel inhibitor of RIPK3, 8904 bioactive compounds were screened for their ability to suppress necroptosis driven by dimerizable RIPK3 (see Methods). Among 64 potential candidates, GW440139B (hereafter referred to as GW'39B) was identified as a promising inhibitor with an EC 50 of 0.0736 μM (Supplementary Figures 3a and b).…”

Section: Resultsmentioning

confidence: 99%

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Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

et al. 2015

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Mixed lineage kinase domain-like pseudokinase (MLKL) mediates necroptosis by translocating to the plasma membrane and inducing its rupture. The activation of MLKL occurs in a multimolecular complex (the 'necrosome'), which is comprised of MLKL, receptor-interacting serine/threonine kinase (RIPK)-3 (RIPK3) and, in some cases, RIPK1. Within this complex, RIPK3 phosphorylates the activation loop of MLKL, promoting conformational changes and allowing the formation of MLKL oligomers, which migrate to the plasma membrane. Previous studies suggested that RIPK3 could phosphorylate the murine MLKL activation loop at Ser345, Ser347 and Thr349. Moreover, substitution of the Ser345 for an aspartic acid creates a constitutively active MLKL, independent of RIPK3 function. Here we examine the role of each of these residues and found that the phosphorylation of Ser345 is critical for RIPK3-mediated necroptosis, Ser347 has a minor accessory role and Thr349 seems to be irrelevant. We generated a specific monoclonal antibody to detect phospho-Ser345 in murine cells. Using this antibody, a series of MLKL mutants and a novel RIPK3 inhibitor, we demonstrate that the phosphorylation of Ser345 is not required for the interaction between RIPK3 and MLKL in the necrosome, but is essential for MLKL translocation, accumulation in the plasma membrane, and consequent necroptosis.

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Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

et al. 2015

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“…In keeping with the wellestablished protective role of NAD + against genotoxic/ oxidative insults, iNam inhibited L929 cell necrosis induced by a genotoxic agent (MNNG) known to cause PARP1-dependent necrosis (Figure 1f). Of particular interest, iNam sensitized murine embryonic fibroblasts (MEFs) to TNFinduced necroptosis, a form of cell death inhibited by both necrostatin-1 ( Figure 1g) and a recently developed specific inhibitor of the kinase activity of RIPK3 (R3i) 26,27 (Supplementary Figure S1), further confirming that independently of the experimental strategy used, intracellular NAD + appears to promote necroptotic cell death. Finally, we examined the capacity of RIPK3 to be recruited into RIPK1-containing complexes upon TNF stimulation.…”

Section: Intracellular Nadmentioning

confidence: 56%

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD + ) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD + promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD + -dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD + does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors. + as a substrate in a number of regulatory processes has shed a new light on its role in cell physiology. Indeed, NAD + represents a substrate for a wide range of enzymes including cADP-ribose synthases, poly (ADP-ribose) polymerases (PARPs) and the sirtuin family of NAD + -dependent deacylases (SIRTs). In marked contrast to its role in energy metabolism, the involvement of NAD + in these enzymatic reactions is based on its ability to function as a donor of ADP-ribose, a reaction that, if sustained, can lead to the depletion of the intracellular NAD + pool. 1-5The pro-survival role of NAD + has been particularly well described in cells exposed to genotoxic/oxidative stress. In response to DNA damage, PARP1, the founding and most abundant member of the PARP family, binds to DNA strand breaks and initiates a repair response by catalyzing the posttranslational modification of several nuclear proteins, including itself. This protective response is characterized by the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD + to other proteins, compromising therefore both energy production (slowing the rate of glycolysis, electron transport and ATP formation) and activity of other NAD + -dependent enzymes through NAD + depletion. 6,7 Moreover, PARP1-synthesized PAR polymers can be degraded into free oligomers, known to translocate to the mitochondria where they can trigger the release of AIF from mitochondria to the nucleus. [8][9][10][11] The precise molecular steps linking PARP1 activation to this form of stress-induced cell death, termed parthanatos, have not been fully elucidated, and...

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“…3C). Similarly, the selective RIP2 inhibitor SB 203580, but not the RIP1 inhibitor Necrostatin-1 (Degterev et al, 2013) nor the RIP3 inhibitor Dabrafenib (Li et al, 2014), was able to significantly increase Bortezomib-induced apoptosis in IM9 and PAX5-expressing RPMI8226 cells (Fig. 3D).…”

Section: Pax5 Induces Drug Resistance By Promoting Rip2 and Nf-κb Actmentioning

confidence: 97%

PAX5 interacts with RIP2 to promote NF-κB activation and drug-resistance in B-lymphoproliferative disorders

Wang

Chen

et al. 2016

Journal of Cell Science

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Paired box protein 5 (PAX5) plays a lineage determination role in B-cell development. However, high expression of PAX5 has been also found in various malignant diseases, including B-lymphoproliferative disorders (B-LPDs), but its functions and mechanisms in these diseases are still unclear. Here, we show that PAX5 induces drug resistance through association and activation of receptor-interacting serine/threonine-protein kinase 2 (RIP2; also known as RIPK2), and subsequent activation of NF-κB signaling and anti-apoptosis gene expression in B-lymphoproliferative cells. Furthermore, PAX5 is able to interact with RIP1 and RIP3, modulating both RIP1-mediated TNFR and RIP2-mediated NOD1 and NOD2 pathways. Our findings describe a new function of PAX5 in regulating RIP1 and RIP2 activation, which is at least involved in chemotherapeutic drug resistance in B-LPDs.

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The B-RafV600E inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury

Cited by 209 publications

References 42 publications

Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

PAX5 interacts with RIP2 to promote NF-κB activation and drug-resistance in B-lymphoproliferative disorders

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