IκΒα inhibits apoptosis at the outer mitochondrial membrane independently of NF ‐κB retention
| العنوان: | IκΒα inhibits apoptosis at the outer mitochondrial membrane independently of |
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| المؤلفون: | Stefan Grimm, Christoph Datler, Eric O. Aboagye, Jan Kroon, Wanwisa Chaisaklert, Ming-Shih Hwang, Ding Qize, Evangelos Pazarentzos, Anne-Laure Mahul-Mellier, Foy Osborne, Amein K. Al-Ali, Abdullah M. Al-Rubaish, Nicholas D. Mazarakis |
| المصدر: | The EMBO Journal. 33:2814-2828 |
| بيانات النشر: | EMBO, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Programmed cell death, Blotting, Western, Oligonucleotides, Apoptosis, Mitochondrion, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Cell Line, Mice, chemistry.chemical_compound, NF-KappaB Inhibitor alpha, Hexokinase, Animals, Humans, Immunoprecipitation, Molecular Biology, Transcription factor, Mice, Inbred BALB C, General Immunology and Microbiology, biology, Voltage-Dependent Anion Channel 1, General Neuroscience, Cytochrome c, NF-kappa B, Cytochromes c, NF-κB, Articles, Flow Cytometry, Xenograft Model Antitumor Assays, Molecular biology, Cell biology, IκBα, Microscopy, Fluorescence, chemistry, Mitochondrial Membranes, biology.protein, Female, I-kappa B Proteins, VDAC1 |
| الوصف: | IκBα resides in the cytosol where it retains the inducible transcription factor NF‐κB. We show that IκBα also localises to the outer mitochondrial membrane (OMM) to inhibit apoptosis. This effect is especially pronounced in tumour cells with constitutively active NF‐κB that accumulate high amounts of mitochondrial IκBα as a NF‐κB target gene. 3T3 IκBα −/− cells also become protected from apoptosis when IκBα is specifically reconstituted at the OMM. Using various IκBα mutants, we demonstrate that apoptosis inhibition and NF‐κB inhibition can be functionally and structurally separated. At mitochondria, IκBα stabilises the complex of VDAC1 and hexokinase II (HKII), thereby preventing Bax recruitment to VDAC1 and the release of cytochrome c for apoptosis induction. When IκBα is reduced in tumour cells with constitutively active NF‐κB, they show an enhanced response to anticancer treatment in an in vivo xenograft tumour model. Our results reveal the unexpected activity of IκBα in guarding the integrity of the OMM against apoptosis induction and open possibilities for more specific interference in tumours with deregulated NF‐κB. |
| تدمد: | 1460-2075 0261-4189 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1f22c24ad83412ee94aca85a10c8ea1fTest https://doi.org/10.15252/embj.201488183Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1f22c24ad83412ee94aca85a10c8ea1f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602075 02614189 |
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