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1.
Cell Death Differ ; 22(3): 377-88, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25257172

RESUMO

Autophagy is a catabolic process aimed at recycling cellular components and damaged organelles in response to diverse conditions of stress, such as nutrient deprivation, viral infection and genotoxic stress. A growing amount of evidence in recent years argues for oxidative stress acting as the converging point of these stimuli, with reactive oxygen species (ROS) and reactive nitrogen species (RNS) being among the main intracellular signal transducers sustaining autophagy. This review aims at providing novel insight into the regulatory pathways of autophagy in response to glucose and amino acid deprivation, as well as their tight interconnection with metabolic networks and redox homeostasis. The role of oxidative and nitrosative stress in autophagy is also discussed in the light of its being harmful for both cellular biomolecules and signal mediator through reversible posttranslational modifications of thiol-containing proteins. The redox-independent relationship between autophagy and antioxidant response, occurring through the p62/Keap1/Nrf2 pathway, is also addressed in order to provide a wide perspective upon the interconnection between autophagy and oxidative stress. Herein, we also attempt to afford an overview of the complex crosstalk between autophagy and DNA damage response (DDR), focusing on the main pathways activated upon ROS and RNS overproduction. Along these lines, the direct and indirect role of autophagy in DDR is dissected in depth.


Assuntos
Autofagia/fisiologia , Estresse Oxidativo/fisiologia , Animais , Homeostase , Humanos , Transdução de Sinais
2.
Cell Death Differ ; 18(3): 516-27, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20966962

RESUMO

Apaf1 is a key regulator of the mitochondrial intrinsic pathway of apoptosis, as it activates executioner caspases by forming the apoptotic machinery apoptosome. Its genetic regulation and its post-translational modification are crucial under the various conditions where apoptosis occurs. Here we describe Ku70/86, a mediator of non-homologous end-joining pathway of DNA repair, as a novel regulator of Apaf1 transcription. Through analysing different Apaf1 promoter mutants, we identified an element repressing the Apaf1 promoter. We demonstrated that Ku70/86 is a nuclear factor able to bind this repressing element and downregulating Apaf1 transcription. We also found that Ku70/86 interaction with Apaf1 promoter is dynamically modulated upon DNA damage. The effect of this binding is a downregulation of Apaf1 expression immediately following the damage to DNA; conversely, we observed Apaf1 upregulation and apoptosis activation when Ku70/86 unleashes the Apaf1-repressing element. Therefore, besides regulating DNA repair, our results suggest that Ku70/86 binds to the Apaf1 promoter and represses its activity. This may help to inhibit the apoptosome pathway of cell death and contribute to regulate cell survival.


Assuntos
Antígenos Nucleares/metabolismo , Fator Apoptótico 1 Ativador de Proteases/genética , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Animais , Antígenos Nucleares/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Dano ao DNA/genética , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Proteínas de Ligação a DNA/química , Etoposídeo/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Autoantígeno Ku , Camundongos , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Transcrição Gênica/efeitos dos fármacos
3.
Cell Death Differ ; 17(7): 1155-66, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20111043

RESUMO

Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been 'designed' to be retained in mitochondria and to minimize its potential neurotoxic activity.


Assuntos
Fator de Indução de Apoptose/metabolismo , Encéfalo/metabolismo , Mitocôndrias/metabolismo , Sequência de Aminoácidos , Animais , Fator de Indução de Apoptose/química , Fator de Indução de Apoptose/genética , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Camundongos , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Dados de Sequência Molecular , Neurônios/citologia , Neurônios/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Alinhamento de Sequência
4.
Cell Mol Life Sci ; 65(11): 1780-90, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18480964

RESUMO

Fas-associated factor 1 (Faf1) has been described as a Fas-binding pro-apoptotic protein and as a component of the death-inducing signaling complex (DISC) in Fas-mediated apoptosis. Faf1 is able to potentiate Fas-induced apoptosis in several cell lines, although its specific functions are still not clear. Here we show that Faf1 is highly expressed in several areas of the developing telencephalon. Its expression pattern appears to be dynamic at different embryonic stages and to be progressively confined within limited territories. To decipher the specific role of Faf1 in developing brain, we used cDNA over-expression and mRNA down-regulation experiments to modulate Faf1 expression in telencephalic neural precursor cells, and we showed that in neural cell death Faf1 acts as a Fas-independent apoptotic enhancer. Moreover, we found that Faf1 protein level is down-regulated during apoptosis in a caspase- and Apaf1-dependent manner.


Assuntos
Fator Apoptótico 1 Ativador de Proteases/metabolismo , Encéfalo/embriologia , Proteínas de Transporte/metabolismo , Caspase 3/metabolismo , Neurônios/metabolismo , Células-Tronco/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose , Fator Apoptótico 1 Ativador de Proteases/genética , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Proteínas de Transporte/genética , Caspase 3/genética , Células Cultivadas , Ativação Enzimática , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Neurônios/citologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Células-Tronco/citologia
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