Evidence map›Paper›PMID 24577082›Full record

ArticleCell death & disease2014

Akt and mTOR mediate programmed necrosis in neurons.

Q Liu, J Qiu, M Liang, J Golinski, K van Leyen, J E Jung, Z You, E H Lo, A Degterev, M J Whalen

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.

0numbers the graph read from it
0cells of the map it votes in
80citing papers in PubMed
4.8field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

80 citing papers in PubMed, 147 citations in OpenAlex.

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20 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 1 country.

Q Liu1] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [3] Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China.
J Qiu1] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
M Liang1] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [3] Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
J Golinski1] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
K van Leyen1] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
J E Jung1] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Z YouDepartment of Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA.
E H Lo1] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
A DegterevDepartment of Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA.
M J Whalen1] Department of Pediatric Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA [2] Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Massachusetts General Hospital · USHarvard University · USTufts University · US

Funding

12-Lipoxygenase and Ischemic Brain Cell DeathR01NS049430 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI VAN LEYEN, KLAUS · 2005 to 2015
$3.6M
NINDS NIH HHS R01 NS049430PHS HHS 5R01NSO64545
6 · The paper itself

Abstract

Necroptosis is a newly described form of regulated necrosis that contributes to neuronal death in experimental models of stroke and brain trauma. Although much work has been done elucidating initiating mechanisms, signaling events governing necroptosis remain largely unexplored. Akt is known to inhibit apoptotic neuronal cell death. Mechanistic target of rapamycin (mTOR) is a downstream effector of Akt that controls protein synthesis. We previously reported that dual inhibition of Akt and mTOR reduced acute cell death and improved long term cognitive deficits after controlled-cortical impact in mice. These findings raised the possibility that Akt/mTOR might regulate necroptosis. To test this hypothesis, we induced necroptosis in the hippocampal neuronal cell line HT22 using concomitant treatment with tumor necrosis factor α (TNFα) and the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. TNFα/zVAD treatment induced cell death within 4 h. Cell death was preceded by RIPK1-RIPK3-pAkt assembly, and phosphorylation of Thr-308 and Thr473 of AKT and its direct substrate glycogen synthase kinase-3β, as well as mTOR and its direct substrate S6 ribosomal protein (S6), suggesting activation of Akt/mTOR pathways. Pretreatment with Akt inhibitor viii and rapamycin inhibited Akt and S6 phosphorylation events, mitochondrial reactive oxygen species production, and necroptosis by over 50% without affecting RIPK1-RIPK3 complex assembly. These data were confirmed using small inhibitory ribonucleic acid-mediated knockdown of AKT1/2 and mTOR. All of the aforementioned biochemical events were inhibited by necrostatin-1, including Akt and mTOR phosphorylation, generation of oxidative stress, and RIPK1-RIPK3-pAkt complex assembly. The data suggest a novel, heretofore unexpected role for Akt and mTOR downstream of RIPK1 activation in neuronal cell death.

Indexed as

AnimalsCaspase InhibitorsCell LineDose-Response Relationship, DrugEnzyme ActivationGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHippocampusImidazolesIndolesMiceMitochondriaNecrosisNeuronsOligopeptidesOxidative StressAkt1 protein, mouseAkt2 protein, mousebenzyloxycarbonyl-valyl-alanyl-aspartic acidCaspase InhibitorsGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaGsk3b protein, mouseImidazolesIndolesmTOR protein, mousenecrostatin-1OligopeptidesProtein Kinase InhibitorsProto-Oncogene Proteins c-aktReactive Oxygen SpeciesReceptor-Interacting Protein Serine-Threonine KinasesRibosomal Protein S6Ripk1 protein, mouseRipk3 protein, mouseTOR Serine-Threonine KinasesTumor Necrosis Factor-alpha

Identifiers

PMID24577082
PMCPMC3944276
OpenAlexW2120723414

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.