title: Involvement of AMPK in regulating the degradation of MAD2B under high glucose in neuronal cells.
abstract: Although our recent study has demonstrated that mitotic spindle assembly checkpoint protein (MAD2B) mediates high glucose-induced neuronal apoptosis, the mechanisms for MAD2B degradation under hyperglycaemia have not yet been elucidated. In this study, we first found that the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) was decreased in neurons, accompanied with the increased expression of MAD2B. Mechanistically, we demonstrated that activation of AMPK with its activators such as AICAR and metformin decreased the expression of MAD2B, indicating a role of AMPK in regulating the expression of MAD2B. Moreover, activation of AMPK prevented neuronal cells from high glucose-induced injury as demonstrated by the reduced expression of cyclin B1 and percentage of apoptosis as detected by TUNEL. We further found that when total protein synthesis was suppressed by chlorhexidine, the degradation of MAD2B was slower in high glucose-treated neurons and was mainly dependent on the ubiquitin-proteasome system. Finally, it was indicated that high glucose inhibited the ubiquitination of MAD2B, which could be reversed by activation of AMPK. Collectively, this study demonstrates that AMPK acts as a key regulator of MAD2B expression, suggesting that activation of AMPK signalling might be crucial for the treatment of high glucose-induced neuronal injury.
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xianfang
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guangpin
authors.initials: G
authors.lastname: Chu
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Ye
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064246:Mad2 Proteins / Q000235:genetics*; D008687:Metformin / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics*; D059748:Proteolysis / Q000187:drug effects; D051381:Rats
chemical_list: C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D008687:Metformin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose
keywords: AMPK; MAD2B; high glucose; neuron; protein degradation