title: Involvement of dysregulated Wip1 in manganese-induced p53 signaling and neuronal apoptosis.
abstract: Overexposure to manganese (Mn) has been known to induce neuronal death and neurodegenerative symptoms. However, the precise mechanisms underlying Mn neurotoxicity remain incompletely understood. In the present study, we established a Mn-exposed rat model and found that downregulation of wild type p53-induced phosphatase 1 (Wip1) might contribute to p53 activation and resultant neuronal apoptosis following Mn exposure. Western blot and immunohistochemical analyses revealed that the expression of Wip1 was markedly decreased following Mn exposure. In addition, immunofluorescence assay demonstrated that Mn exposure led to significant reduction in the number of Wip1-positive neurons. Accordingly, the expression of Mdm2 was progressively decreased, which was accompanied with markedly increased expression of p53, as well as the ratio of Bax/Bcl-xl. Furthermore, we showed that Mn exposure decreased the viability and induced apparent apoptosis in NFG-differentiated neuron-like PC12 cells. Importantly, the expression of Wip1 decreased progressively, whereas the level of cellular p53 and the ratio of Bax/Bcl-xl were elevated, which resembled the expression of the proteins in animal model studies. Depletion of p53 significantly ameliorated Mn-mediated cytotoxic effect in PC12 cells. In addition, ectopic expression of Wip1 attenuated Mn-induced p53 signaling as well as apoptosis in PC12 cells. Finally, we observed that depletion of Wip1 augmented Mn-induced apoptosis in PC12 cells. Collectively, these findings suggest that downregulated Wip1 expression plays an important role in Mn-induced neuronal death in the brain striatum via the modulation of p53 signaling.
authors: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors: Xia
authors: X
authors: Ma
authors: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors: Jingling
authors: J
authors: Han
authors: The Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China.
authors: Qiyun
authors: Q
authors: Wu
authors: The Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China.
authors: Hanzhang
authors: H
authors: Liu
authors: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors: Shangshi
authors: S
authors: Shi
authors: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors: Cheng
authors: C
authors: Wang
authors: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors: Yueran
authors: Y
authors: Wang
authors: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors: Jing
authors: J
authors: Xiao
authors: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, People's Republic of China.
authors: Jianya
authors: J
authors: Zhao
authors: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, People's Republic of China; The Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China. Electronic address: Jiang_junkang@163.com.
authors: Junkang
authors: J
authors: Jiang
authors: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, People's Republic of China; The Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, People's Republic of China. Electronic address: Chwan@ntu.edu.cn.
authors: Chunhua
authors: C
authors: Wan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001479:Basal Ganglia / Q000201:enzymology* / Q000473:pathology; D002712:Chlorides; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D017895:Manganese Compounds; D020149:Manganese Poisoning / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D002712:Chlorides; D017895:Manganese Compounds; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; C025340:manganese chloride
keywords: Apoptosis; Manganese; Neurotoxicity; Striatum; Wip1; p53