title: Nuclear translocation of annexin 1 following oxygen-glucose deprivation-reperfusion induces apoptosis by regulating Bid expression via p53 binding.
abstract: Previous data have suggested that the nuclear translocation of annexin 1 (ANXA1) is involved in neuronal apoptosis after ischemic stroke. As the mechanism and function of ANXA1 nuclear migration remain unclear, it is important to clarify how ANXA1 performs its role as an apoptosis 'regulator' in the nucleus. Here we report that importazole (IPZ), an importin β (Impβ)-specific inhibitor, decreased ANXA1 nuclear accumulation and reduced the rate of neuronal death induced by nuclear ANXA1 migration after oxygen-glucose deprivation-reoxygenation (OGD/R). Notably, ANXA1 interacted with the Bid (BH3-interacting-domain death agonist) promoter directly; however; this interaction could be partially blocked by the p53 inhibitor pifithrin-α (PFT-α). Accordingly, ANXA1 was shown to interact with p53 in the nucleus and this interaction was enhanced following OGD/R. A luciferase reporter assay revealed that ANXA1 was involved in the regulation of p53-mediated transcriptional activation after OGD/R. Consistent with this finding, the nuclear translocation of ANXA1 after OGD/R upregulated the expression of Bid, which was impeded by IPZ, ANXA1 shRNA, or PFT-α. Finally, cell-survival testing demonstrated that silencing ANXA1 could improve the rate of cell survival and decrease the expression of both cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. These data suggested that Impβ-dependent nuclear ANXA1 migration participates in the OGD/R-dependent induction of neuronal apoptosis. ANXA1 interacts with p53 and promotes p53 transcriptional activity, which in turn regulates Bid expression. Silencing ANXA1 decreases the expression of Bid and suppresses caspase-3 pathway activation, thus improving cell survival after OGD/R. This study provides a novel mechanism whereby ANXA1 regulates apoptosis, suggesting the potential for a previously unidentified treatment strategy in minimizing apoptosis after OGD/R.
authors: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, People's Republic of China.|Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Xing
authors: X
authors: Li
authors: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Yin
authors: Y
authors: Zhao
authors: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, People's Republic of China.|Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Qian
authors: Q
authors: Xia
authors: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, People's Republic of China.|Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Lu
authors: L
authors: Zheng
authors: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, People's Republic of China.|Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Lu
authors: 0000-0002-4788-1445
authors: L
authors: Liu
authors: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, People's Republic of China.|Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Baoming
authors: B
authors: Zhao
authors: Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.|Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, People's Republic of China.|Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors: Jing
authors: J
authors: Shi
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency*; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D014176:Protein Biosynthesis / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism
chemical_list: D017305:Annexin A1; D051023:BH3 Interacting Domain Death Agonist Protein; D016159:Tumor Suppressor Protein p53; D028961:beta Karyopherins; D053148:Caspase 3; D005947:Glucose; D010100:Oxygen