RESUMEN
BACKGROUND: To address the functional roles of genetic polymorphisms of brain-derived neurotrophic factor (BDNF) in Alzheimer's disease (AD) from a neuropsychological aspect, we used a cross-sectional study design to investigate the association between novel single nucleotide polymorphisms (SNPs) of the BDNF gene (Val66Met (G196A) and C270T) and the Frontal Assessment Battery (FAB) score, which reflects executive function as a non-memory cognitive impairment. METHODS: One hundred and sixty-nine outpatients with AD or amnestic mild cognitive impairment (A-MCI) were recruited to the study and divided into three genotypic groups for each representative BDNF functional polymorphism as follows: (i) Val66Met (G196A): G/G (n = 45), G/A (n = 104), and A/A (n = 20); and (ii) C270T: C/C (n = 160), C/T (n = 9), and T/T (n = 0). Then, age, sex ratio, duration of illness (months), education years, Mini-Mental State Examination (MMSE) score, behavioral pathology in Alzheimer disease (Behave-AD) score, Clinical Dementia Rating (CDR) ratio, and total and subtest FAB scores were compared between the genotypic groups for each SNP. RESULTS: Significant differences were found in the total (P < 0.01) and subtest (conflicting instructions and prehension behavior; P < 0.01) FAB scores between the C270T polymorphism groups (C/C and C/T), but not among the G196A polymorphism groups. However, no significant differences in age, sex ratio, duration of illness (months), education years, Behave-AD score, CDR ratio, or MMSE score (reflecting attention and memory function) were found between the individual polymorphism genotypes (G196A and C270T). CONCLUSION: Of the known BDNF polymorphisms, the C270T SNP may influence executive dysfunction as a non-memory cognitive impairment in Japanese patients with AD.
Asunto(s)
Alelos , Enfermedad de Alzheimer/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Disfunción Cognitiva/genética , Función Ejecutiva , Polimorfismo Genético/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Japón , Masculino , Escala del Estado Mental/estadística & datos numéricos , Pruebas Neuropsicológicas/estadística & datos numéricos , Polimorfismo de Nucleótido Simple/genética , Psicometría , Factores de Riesgo , Factores Sexuales , Estadística como AsuntoRESUMEN
We evaluated the molecular mechanism of telomerase activation by erythropoietin (EPO) in human erythroleukemic JAS-REN-A cells. Telomerase activity increased 3-4 fold after 3-24h of culture with EPO and was associated with increases in c-myc mRNA after 1-3h, of c-Myc protein after 3-6h, and of human telomerase reverse transcriptase (hTERT) mRNA and hTERT protein after 6-24h. Simultaneously EPO induced phosphorylation of signal transducer activator of transcription 5 (STAT5), AKT, and extracellular signal-regulated kinase (ERK). Telomerase activity induced by EPO was significantly inhibited by AG490, PD98059, and LY294002. AG490 downregulated c-myc and hTERT mRNA expression with inhibited STAT5 and AKT phosphorylation. PD98059 also reduced c-myc and hTERT expression and inhibited ERK phosphorylation. However, LY294002 did not inhibit c-myc or hTERT mRNA expression despite inhibiting STAT5 and AKT phosphorylation. These results suggest that EPO activates telomerase in JAS-REN-A cells through dual regulation: hTERT gene transcription by Janus tyrosine kinase 2/STAT5/c-Myc and hTERT protein phosphorylation by phosphatidylinositol 3'-kinase/AKT.
Asunto(s)
Eritropoyetina/farmacología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Leucemia Eritroblástica Aguda/tratamiento farmacológico , Leucemia Eritroblástica Aguda/enzimología , Telomerasa/genética , Transcripción Genética/efectos de los fármacos , Western Blotting , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Flavonoides/farmacología , Humanos , Leucemia Eritroblástica Aguda/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , Proteínas Recombinantes , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Telomerasa/metabolismo , Células Tumorales CultivadasRESUMEN
Although p53 is intact in most cases of retinoblastoma, it is largely inactivated by the ubiqutin-proteasome system through interaction with murine double minute 2 (MDM2) and murine double minute X (MDMX). The present study showed that the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and depsipeptide (FK228) synergistically enhanced ionizing radiation (IR)-induced apoptosis, associated with activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in Y79 and WER1-Rb1 human retinoblastoma cells. Both VPA and FK228 enhanced IR-induced phosphorylation of histone H2AX on Ser139 preceding apoptosis. Exposure of cells to IR in the presence of VPA or FK228 induced the accumulation of p53 acetylated at Lys382 and phosphorylated at Ser46 through the reduction of binding affinity with MDM2 and MDMX. These results suggest that acetylation of p53 by HDAC inhibitors is a promising new therapeutic target in refractory retinoblastoma.