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

Autor: Irene Sánchez-Morán, Marta Domínguez-Martínez, José Castillo, José C. Gómez-Sánchez, Cristina Rodríguez, María E. Ramos-Araque, Juan P. Bolaños, Angeles Almeida, Jesús Agulla, Maria Delgado-Esteban, Tomás Sobrino
Přispěvatelé: Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Junta de Castilla y León
Rok vydání: 2018
Předmět:
0301 basic medicine
Original Contributions
Apoptosis
Cerebral hemorrhage
Brain ischemia
0302 clinical medicine
Risk Factors
Modified Rankin Scale
Gene knockdown
biology
apoptosis
Proto-Oncogene Proteins c-mdm2
Prognosis
stroke
Ubiquitin ligase
Stroke
alleles
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Mdm2
Cardiology and Cardiovascular Medicine
medicine.medical_specialty
Genotype
Ischemia
Polymorphism
Single Nucleotide
03 medical and health sciences
Internal medicine
medicine
Animals
Humans
Genetic Predisposition to Disease
neoplasms
Alleles
Advanced and Specialized Nursing
Intracerebral hemorrhage
cerebral hemorrhage
Basic Sciences
business.industry
Recovery of Function
medicine.disease
brain ischemia
Mice
Inbred C57BL
enzymes and coenzymes (carbohydrates)
030104 developmental biology
Endocrinology
biology.protein
prognosis
Neurology (clinical)
business
030217 neurology & neurosurgery
Zdroj: Stroke
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1524-4628
0039-2499
DOI: 10.1161/strokeaha.118.022529
Popis: [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.
This work was funded by Instituto de Salud Carlos III (PI15/00473, RD16/0019/0018, and RD16/0019/0001), European Regional Development Fund, Ministerio de Economía y Competitividad (SAF2016-78114-R), European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement 686009), and Junta de Castilla y León (IES007P17). Drs Rodríguez (RD16/0019/0018), Delgado-Esteban (CP0014/00010), and Sobrino (CPII17/00027) are supported by Instituto de Salud Carlos III.
Databáze: OpenAIRE
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