title: The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke.
abstract: The functional outcome after stroke is unpredictable; it is not accurately predicted by clinical pictures upon hospital admission. The presence of apoptotic neurons in the ischemic penumbra and perihematoma area may account for poor prognosis, but whether the highly variable stroke outcome reflects differences in genetic susceptibility to apoptosis is elusive. The p53 tumor suppressor protein, an important transcriptional regulator of apoptosis, naturally occurs in humans in two variants with single nucleotide polymorphisms resulting in Arg or Pro at residue 72. We show that poor functional outcome after either ischemic or hemorrhagic stroke was linked to the Arg/Arg genotype. This genotype was also associated with early neurological deterioration in ischemic stroke and with increased residual cavity volume in intracerebral hemorrhage. In primary cultured neurons, Arg(72)-p53, but not Pro(72)-p53, interacted directly with mitochondrial Bcl-xL and activated the intrinsic apoptotic pathway, increasing vulnerability to ischemia-induced apoptotic cell death. These results suggest that the Tp53 Arg/Arg genotype governs neuronal vulnerability to apoptosis and can be considered as a genetic marker predicting poor functional outcome after stroke.
authors.affiliation: Department of Neurology, University Hospital of Salamanca, 37007 Salamanca, Spain.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Gomez-Sanchez
authors.forename: Maria
authors.initials: M
authors.lastname: Delgado-Esteban
authors.forename: Irene
authors.initials: I
authors.lastname: Rodriguez-Hernandez
authors.forename: Tomas
authors.initials: T
authors.lastname: Sobrino
authors.forename: Natalia
authors.initials: N
authors.lastname: Perez de la Ossa
authors.forename: Silvia
authors.initials: S
authors.lastname: Reverte
authors.forename: Juan P
authors.initials: JP
authors.lastname: Bolaños
authors.forename: Rogelio
authors.initials: R
authors.lastname: Gonzalez-Sarmiento
authors.forename: Jose
authors.initials: J
authors.lastname: Castillo
authors.forename: Angeles
authors.initials: A
authors.lastname: Almeida
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000235:genetics / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics / Q000502:physiology; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000502:physiology; D011379:Prognosis; D020521:Stroke / Q000175:diagnosis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
chemical_list: D005819:Genetic Markers; D016159:Tumor Suppressor Protein p53