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1.
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
2.
Oncogene ; 27(30): 4221-32, 2008 Jul 10.
Article in English | MEDLINE | ID: mdl-18362892

ABSTRACT

Following the screening of a battery of distinct small-interfering RNAs that target various components of the apoptotic machinery, we found that knockdown of the voltage-dependent anion channel 1 (VDAC1) was particularly efficient in preventing cell death induced by cisplatin (CDDP) in non-small cell lung cancer cells. Both the downregulation of VDAC1 and its chemical inhibition with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid reduced the apoptosis-associated modifications induced by CDDP, including mitochondrial transmembrane potential dissipation and plasma membrane permeabilization. VDAC1 inhibition strongly reduced the CDDP-induced conformational activation of Bax, yet had no discernible effect on the activation of Bak, suggesting that VDAC1 acts downstream of Bak and upstream of Bax. Accordingly, knockdown of Bak abolished the activation of Bax, whereas Bax downregulation had no effect on Bak activation. In VDAC1-depleted cells, the failure of CDDP to activate Bax could be reversed by means of the Bcl-2/Bcl-X(L) antagonist ABT-737, which concomitantly restored CDDP cytotoxicity. Altogether, these results delineate a novel pathway for the induction of mitochondrial membrane permeabilization (MMP) in the course of CDDP-induced cell death that involves a hierarchical contribution of Bak, VDAC1 and Bax. Moreover, our data suggest that VDAC1 may act as a facultative regulator/effector of MMP, depending on the initial cytotoxic event.


Subject(s)
Apoptosis/drug effects , Cisplatin/pharmacology , Signal Transduction/drug effects , Voltage-Dependent Anion Channel 1/physiology , bcl-2 Homologous Antagonist-Killer Protein/physiology , bcl-2-Associated X Protein/physiology , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/genetics , Biphenyl Compounds/pharmacology , Cell Death/drug effects , Cell Death/genetics , Cell Membrane Permeability/drug effects , Drug Synergism , HCT116 Cells , HeLa Cells , Humans , Models, Biological , Nitrophenols/pharmacology , Piperazines/pharmacology , Signal Transduction/genetics , Sulfonamides/pharmacology , Tumor Cells, Cultured , Voltage-Dependent Anion Channel 1/antagonists & inhibitors
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