A Receptor-interacting Protein 1 (RIP1)-independent Necrotic Death under the Control of Protein Phosphatase PP2A That Involves the Reorganization of Actin Cytoskeleton and the Action of Cofilin-1

Tomasella, Andrea; Blangy, Anne; Brancolini, Claudio

doi:10.1074/jbc.m114.575134

Cited by 20 publications

(36 citation statements)

References 55 publications

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“…S3c). On the opposite it is strongly dependent on the activity of RIP1, as previously reported 13 . Hence, GSK3β kinase activity is necessary to trigger cell death in response to DMNQ.…”

Section: Gsk3β Kinase Activity Is Required For Dmnq-induced Oxidativesupporting

confidence: 83%

“…To validate CAPN1 as an effector of the G5-induced necrosis, we silenced its expression using a siRNA targeting a different region of the gene. In addition, a siRNA against PP2AC was used as positive control 13 .…”

Section: Validation Of Capn1 and Gsk3β As Genes Transducing G5inducedmentioning

confidence: 99%

“…G5 triggers pleiotropic stresses, which can drive cells to death through different pathways. Proteasome impairment, misfolding and proteotoxic stress, oxidative stress and cytoskeletal malfunctions are all hallmarks of the G5induced cell death [11][12][13][14] . The partial impact of GSK3β could stem from the co-existence of these multiple pathways.…”

Section: Gsk3β Is a Critical Transducer Of Dmnq-induced Oxidative Deathmentioning

confidence: 99%

“…G5 is a non-selective isopeptidases inhibitor that can react with cellular thiols, thus eliciting multiple cellular stresses [10][11][12][13][14][15] . G5 belongs to a family of compounds that have been synthetized and investigated for the ability to commend accidental death in cancer cells, with therapeutic perspectives [16][17][18][19][20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

“…Protein misfolding, ER-stress, deubiquitinases inhibition and accumulation of polyubiquitylated proteins, glutathione depletion, alterations of the actin cytoskeleton and of the cell adhesion mark the cellular response to G5. In cells resistant to apoptosis this plethora of stresses can result in a necrotic death, which is distinguishable from necroptosis 11,13,14 . However, few additional data are available about the signaling networks transducing this peculiar form of necrosis.…”

Section: Introductionmentioning

confidence: 99%

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GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

et al. 2020

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Signaling pathways controlling necrosis are still mysterious and debated. We applied a shRNA-based viability screen to identify critical elements of the necrotic response. We took advantage from a small molecule (G5) that makes covalent adducts with free thiols by Michael addition and elicits multiple stresses. In cells resistant to apoptosis, G5 triggers necrosis through the induction of protein unfolding, glutathione depletion, ER stress, proteasomal impairments, and cytoskeletal stress. The kinase GSK3β was isolated among the top hits of the screening. Using the quinone DMNQ, a ROS generator, we demonstrate that GSK3β is involved in the regulation of ROS-dependent necrosis. Our results have been validated using siRNA and by knocking-out GSK3β with the CRISPR/Cas9 technology. In response to DMNQ GSK3β is activated by serine 9 dephosphorylation, concomitantly to Akt inactivation. During the quinone-induced pronecrotic stress, GSK3β gradually accumulates into the nucleus, before the collapse of the mitochondrial membrane potential. Accumulation of ROS in response to DMNQ is impaired by the absence of GSK3β. We provide evidence that the activities of the obligatory two-electrons reducing flavoenzymes, NQO1 (NAD(P)H quinone dehydrogenase 1) and NQO2 are required to suppress DMNQ-induced necrosis. In the absence of GSK3β the expression of NQO1 and NQO2 is dramatically increased, possibly because of an increased transcriptional activity of NRF2. In summary, GSK3β by blunting the anti-oxidant response and particularly NQO1 and NQO2 expression, favors the appearance of necrosis in response to ROS, as generated by the quinone DMNQ.

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“…S3c). On the opposite it is strongly dependent on the activity of RIP1, as previously reported 13 . Hence, GSK3β kinase activity is necessary to trigger cell death in response to DMNQ.…”

Section: Gsk3β Kinase Activity Is Required For Dmnq-induced Oxidativesupporting

confidence: 83%

Section: Validation Of Capn1 and Gsk3β As Genes Transducing G5inducedmentioning

confidence: 99%

Section: Gsk3β Is a Critical Transducer Of Dmnq-induced Oxidative Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

et al. 2020

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Actin dynamics and cofilin‐actin rods in alzheimer disease

2016

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Cytoskeletal abnormalities and synaptic loss, typical of both familial and sporadic Alzheimer disease (AD), are induced by diverse stresses such as neuroinflammation, oxidative stress, and energetic stress, each of which may be initiated or enhanced by proinflammatory cytokines or amyloid-β (Aβ) peptides. Extracellular Aβ-containing plaques and intracellular phospho-tau-containing neurofibrillary tangles are postmortem pathologies required to confirm AD and have been the focus of most studies. However, AD brain, but not normal brain, also have increased levels of cytoplasmic rod-shaped bundles of filaments composed of ADF/cofilin-actin in a 1:1 complex (rods). Cofilin, the major ADF/cofilin isoform in mammalian neurons, severs actin filaments at low cofilin/actin ratios and stabilizes filaments at high cofilin/actin ratios. It binds cooperatively to ADP-actin subunits in F-actin. Cofilin is activated by dephosphorylation and may be oxidized in stressed neurons to form disulfide-linked dimers, required for bundling cofilin-actin filaments into stable rods. Rods form within neurites causing synaptic dysfunction by sequestering cofilin, disrupting normal actin dynamics, blocking transport, and exacerbating mitochondrial membrane potential loss. Aβ and proinflammatory cytokines induce rods through a cellular prion protein-dependent activation of NADPH oxidase and production of reactive oxygen species. Here we review recent advances in our understanding of cofilin biochemistry, rod formation, and the development of cognitive deficits. We will then discuss rod formation as a molecular pathway for synapse loss that may be common between all three prominent current AD hypotheses, thus making rods an attractive therapeutic target.

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CoCr‐enriched medium modulates integrin‐based downstream signaling and requires a set of inflammatory genes reprograming in vitro

Fernandes

Bezerra

Carmo

et al. 2017

J Biomedical Materials Res

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Significant health concerns have been raised by the high levels of Cr and Co ions into whole blood as resulted of corrosion process released from biomedical implants, but very little is known about their biological behavior in governing cell metabolism. Thus, we prompted to address this issue by exploring the effects of CoCr enriched medium on both fibroblast and preosteoblast (pre-Ob) cells. First, we showed there is a significant difference in Co and Cr releasing dependent on engineered surface, it being even more released in dual acid-etching treating surface (named w/DAE) than the machined surfaces (named wo/DAE). Thereafter, we showed CoCr affects pre-osteoblast and fibroblast metabolism by dynamically modulating integrin-based downstream signaling (FAK, Src, Rac1, and Cofilin). Specifically on this matter, we have shown there is dynamic β1-integrin gene activation up 24 h in both preosteoblast and fibroblast. Our analysis showed also that both pre-Ob and fibroblast are important resource of proinflammatory cytokines when responding to CoCr enriched medium. In addition, survival-related signaling pathway was also affected interfering on survival and proliferating signal, mainly affecting CDK2, mapk-Erk and mapk-p38 phosphorylations, while AKT/PKB-related gene remained active. In addition, during cell adhesion PP2A (an important Ser/Thr phosphatase) was inactive in both cell lineages and it seems be a CoCr's molecular fingerprint, regulating specific metabolic pathways involved with cytoskeleton rearrangement. Altogether, our results showed for the first time CoCr affects cellular performance in vitro by modulating integrin activation-based downstream signaling and requiring a reprograming of inflammatory genes activations in vitro. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 839-849, 2018.

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A Receptor-interacting Protein 1 (RIP1)-independent Necrotic Death under the Control of Protein Phosphatase PP2A That Involves the Reorganization of Actin Cytoskeleton and the Action of Cofilin-1

Cited by 20 publications

References 55 publications

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

Actin dynamics and cofilin‐actin rods in alzheimer disease

CoCr‐enriched medium modulates integrin‐based downstream signaling and requires a set of inflammatory genes reprograming in vitro

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