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1.
Cerebellum ; 15(4): 509-17, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26374457

RESUMO

Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase, an enzyme that elongates telomeres at the ends of chromosomes during DNA replication. Recently, it was shown that TERT has additional roles in cell survival, mitochondrial function, DNA repair, and Wnt signaling, all of which are unrelated to telomeres. Here, we demonstrate that TERT is enriched in Purkinje neurons, but not in the granule cells of the adult mouse cerebellum. TERT immunoreactivity in Purkinje neurons is present in the nucleus, mitochondria, and cytoplasm. Furthermore, TERT co-localizes with mitochondrial markers, and immunoblot analysis of protein extracts from isolated mitochondria and synaptosomes confirmed TERT localization in mitochondria. TERT expression in Purkinje neurons increased significantly in response to two stressors: a sub-lethal dose of X-ray radiation and exposure to a high glutamate concentration. While X-ray radiation increased TERT levels in the nucleus, glutamate exposure elevated TERT levels in mitochondria. Our findings suggest that in mature Purkinje neurons, TERT is present both in the nucleus and in mitochondria, where it may participate in adaptive responses of the neurons to excitotoxic and radiation stress.


Assuntos
Citosol/enzimologia , Ácido Glutâmico/toxicidade , Mitocôndrias/enzimologia , Células de Purkinje/enzimologia , Lesões Experimentais por Radiação/enzimologia , Telomerase/metabolismo , Animais , Núcleo Celular/enzimologia , Núcleo Celular/patologia , Núcleo Celular/efeitos da radiação , Citosol/patologia , Citosol/efeitos da radiação , Dano ao DNA/fisiologia , Dano ao DNA/efeitos da radiação , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Imunofluorescência , Immunoblotting , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/patologia , Mitocôndrias/efeitos da radiação , Células de Purkinje/patologia , Células de Purkinje/efeitos da radiação , Lesões Experimentais por Radiação/patologia , Estresse Fisiológico/fisiologia , Estresse Fisiológico/efeitos da radiação , Telomerase/genética , Técnicas de Cultura de Tecidos , Raios X/efeitos adversos
2.
Dev Cell ; 37(1): 15-33, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27052834

RESUMO

How cells avoid excessive caspase activity and unwanted cell death during apoptotic caspase-mediated removal of large cellular structures is poorly understood. We investigate caspase-mediated extrusion of spermatid cytoplasmic contents in Drosophila during spermatid individualization. We show that a Krebs cycle component, the ATP-specific form of the succinyl-CoA synthetase ß subunit (A-Sß), binds to and activates the Cullin-3-based ubiquitin ligase (CRL3) complex required for caspase activation in spermatids. In vitro and in vivo evidence suggests that this interaction occurs on the mitochondrial surface, thereby limiting the source of CRL3 complex activation to the vicinity of this organelle and reducing the potential rate of caspase activation by at least 60%. Domain swapping between A-Sß and the GTP-specific SCSß (G-Sß), which functions redundantly in the Krebs cycle, show that the metabolic and structural roles of A-Sß in spermatids can be uncoupled, highlighting a moonlighting function of this Krebs cycle component in CRL activation.


Assuntos
Caspases/metabolismo , Ciclo do Ácido Cítrico/fisiologia , Proteínas Culina/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Mitocôndrias/metabolismo , Espermátides/metabolismo , Animais , Apoptose/fisiologia , Ativação Enzimática , Masculino , Proteínas dos Microfilamentos/metabolismo , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Espermátides/crescimento & desenvolvimento , Succinato-CoA Ligases/metabolismo
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