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1.
Cell Death Differ ; 18(3): 516-27, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20966962

ABSTRACT

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.


Subject(s)
Antigens, Nuclear/metabolism , Apoptotic Protease-Activating Factor 1/genetics , DNA Damage , DNA Repair , DNA-Binding Proteins/metabolism , Animals , Antigens, Nuclear/chemistry , Cell Death/drug effects , Cell Line , DNA Damage/genetics , DNA Repair/drug effects , DNA Repair/genetics , DNA-Binding Proteins/chemistry , Etoposide/pharmacology , Gene Expression Regulation/drug effects , Humans , Hydrogen Peroxide/pharmacology , Ku Autoantigen , Mice , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , Repressor Proteins/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Transcription, Genetic/drug effects
2.
Cell Death Differ ; 17(7): 1155-66, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20111043

ABSTRACT

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.


Subject(s)
Apoptosis Inducing Factor/metabolism , Brain/metabolism , Mitochondria/metabolism , Amino Acid Sequence , Animals , Apoptosis Inducing Factor/chemistry , Apoptosis Inducing Factor/genetics , Apoptosis Regulatory Proteins/chemistry , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Cell Differentiation , Cell Line, Tumor , Humans , Mice , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Molecular Sequence Data , Neurons/cytology , Neurons/metabolism , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/metabolism , Sequence Alignment
3.
Cell Mol Life Sci ; 65(11): 1780-90, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18480964

ABSTRACT

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.


Subject(s)
Apoptotic Protease-Activating Factor 1/metabolism , Brain/embryology , Carrier Proteins/metabolism , Caspase 3/metabolism , Neurons/metabolism , Stem Cells/metabolism , Adaptor Proteins, Signal Transducing , Animals , Apoptosis/physiology , Apoptosis Regulatory Proteins , Apoptotic Protease-Activating Factor 1/genetics , Brain/anatomy & histology , Brain/metabolism , Carrier Proteins/genetics , Caspase 3/genetics , Cells, Cultured , Enzyme Activation , Humans , Intracellular Signaling Peptides and Proteins , Mice , Neurons/cytology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Stem Cells/cytology
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