Evidence map›Paper›PMID 30355102›Full record

ArticleStroke2018

Single-Nucleotide Polymorphism 309T>G in the MDM2 Promoter Determines Functional Outcome After Stroke.

Cristina Rodríguez, María E Ramos-Araque, Marta Domínguez-Martínez, Tomás Sobrino, Irene Sánchez-Morán, Jesús Agulla, María Delgado-Esteban, José C Gómez-Sánchez, Juan P Bolaños, José Castillo and 1 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Stroke, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed, 1 pooled it
0.9field-weighted citation impact, top 21% 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

17 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.

  1. Influences of genetic variants on stroke recovery: a meta-analysis of the 31,895 cases.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2019
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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

11 authors at 5 institutions in 2 countries.

Cristina RodríguezFrom the Institute of Biomedical Research of Salamanca, University Hospital of Salamanca (C.R., M.E.R.-A., I.S.-M., M.D.-E., J.C.G.-S., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
María E Ramos-AraqueFrom the Institute of Biomedical Research of Salamanca, University Hospital of Salamanca (C.R., M.E.R.-A., I.S.-M., M.D.-E., J.C.G.-S., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
Marta Domínguez-MartínezInstitute of Functional Biology and Genomics (C.R., M.E.R.-A., M.D.-M., I.S.-M., M.D.-E., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
Tomás SobrinoClinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela, Hospital Clínico Universitario, Universidade de Santiago de Compostela, Spain (T.S., J.C.).
Irene Sánchez-MoránFrom the Institute of Biomedical Research of Salamanca, University Hospital of Salamanca (C.R., M.E.R.-A., I.S.-M., M.D.-E., J.C.G.-S., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
Jesús AgullaInstitute of Biology and Molecular Genetics, University of Valladolid, CSIC, Spain (J.A.).
María Delgado-EstebanFrom the Institute of Biomedical Research of Salamanca, University Hospital of Salamanca (C.R., M.E.R.-A., I.S.-M., M.D.-E., J.C.G.-S., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
José C Gómez-SánchezFrom the Institute of Biomedical Research of Salamanca, University Hospital of Salamanca (C.R., M.E.R.-A., I.S.-M., M.D.-E., J.C.G.-S., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
Juan P BolañosFrom the Institute of Biomedical Research of Salamanca, University Hospital of Salamanca (C.R., M.E.R.-A., I.S.-M., M.D.-E., J.C.G.-S., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
José CastilloClinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela, Hospital Clínico Universitario, Universidade de Santiago de Compostela, Spain (T.S., J.C.).
Angeles AlmeidaFrom the Institute of Biomedical Research of Salamanca, University Hospital of Salamanca (C.R., M.E.R.-A., I.S.-M., M.D.-E., J.C.G.-S., J.P.B., A.A.), University of Salamanca, Consejo Superior de Investigaciones Científicas (CSIC), Spain.
Consejo Superior de Investigaciones Científicas · ESInstituto de Biología Funcional y Genómica · ESUniversidad de Salamanca · ESUniversidade de Santiago de Compostela · ESUniversidad de Valladolid · ES

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Background and Purpose- The E3 ubiquitin ligase MDM2 (murine double minute 2) is the main negative regulator of the p53 protein-a key player in neuronal apoptosis after ischemia. A functional single-nucleotide polymorphism in the human MDM2 gene promoter (rs2279744) regulates MDM2 protein expression. We investigated whether the MDM2 SNP309, by controlling p53-mediated apoptosis, determines functional outcome after stroke. Methods- Primary cortical neurons were subjected to oxygen and glucose deprivation. Mice were subjected to ischemic (transient middle cerebral artery occlusion) or hemorrhagic (collagenase injection) stroke models. Protein and mRNA levels of MDM2 and p53 were measured in both neuronal and brain extracts. The interaction of MDM2 with p53 was disrupted by neuronal treatment with nutlin-3a. siRNA was used to knockdown MDM2 expression. We analyzed the link between the MDM2 SNP309 and functional outcome, measured by the modified Rankin Scale scores, in 2 independent hospital-based stroke cohorts: ischemic stroke cohort (408 patients) and intracerebral hemorrhage cohort (128 patients). Results- Experimental stroke and oxygen and glucose deprivation induced the expression of MDM2 in the brain and neurons, respectively. Moreover, oxygen and glucose deprivation promoted MDM2 binding with p53 in neurons. Disruption of the MDM2-p53 interaction with nutlin-3a, or MDM2 knockdown by siRNA, triggered p53 accumulation, which increased neuronal susceptibility to oxygen and glucose deprivation-induced apoptosis. Finally, we showed that patients harboring the G allele in the MDM2 promoter had higher MDM2 protein levels and showed better functional outcome after stroke than those harboring the T/T genotype. The T/T genotype was also associated with large infarct volume in ischemic stroke and increased lesion volume in patients with intracerebral hemorrhage. Conclusions- Our results reveal a novel role for the MDM2-p53 interaction in neuronal apoptosis after ischemia and show that the MDM2 SNP309 determines the functional outcome of patients after stroke.

Indexed as

Genetic Predisposition to DiseasePolymorphism, Single NucleotideAllelesAnimalsGenotypeHumansMice, Inbred C57BLProto-Oncogene Proteins c-mdm2Recovery of FunctionRisk FactorsStrokeMDM2 protein, humanMdm2 protein, mouseProto-Oncogene Proteins c-mdm2allelesapoptosisbrain ischemiacerebral hemorrhageprognosisstroke

Identifiers

PMID30355102
PMCPMC6159670
OpenAlexW2894109484

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.