title: Manganese induces p21 expression in PC12 cells at the transcriptional level.
abstract: Manganese is a common environmental and occupational pollutant. Excessive intake of manganese can cause toxicity known as manganism. Recently it has been demonstrated that unusual expression of cell cycle proteins and aberrant cell cycle progression in the central nervous system are involved in the pathogenesis of neurodegenerative diseases. The present studies were initiated to investigate whether p21 are induced after manganese exposure and its potential effects in vitro, with particular attention being given to understand the underlying regulatory mechanism of p21 induction by manganese in this process. We found that manganese induced DAergic cells injury and upregulation of p21 levels in nigrostriatal regions. Treatment of the PC12 cells with manganese resulted in a time- and concentration-dependent loss of cell viability. Analysis of cell cycle profile indicated that manganese blocked cell cycle progression by arresting the cell cycle at G2/M phase. Moreover, manganese treatment resulted in an increase in the mRNA and protein levels of p21, but did not have the same effect on other related factors. Silencing p21 by RNA interference showed a marked reversal of both G2/M arrest and the decrease in cell viability induced by manganese. Manganese did not stabilize the p21 protein and mRNA, and caused a marked increase in p21 mRNA levels together with an increase in its promoter activity, indicating a transcriptional mechanism. Overall, the in vivo and in vitro data suggest that exposure to manganese can increase p21 levels. An altered cell cycle status of PC12 cells can be induced by manganese through p21 up-regulation, and the induction of p21 occurs at the transcriptional level via promoter activation and mRNA induction.
authors.affiliation: Department of Occupational and Environmental Health and The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhao
authors.forename: J-B
authors.initials: JB
authors.lastname: Zhang
authors.forename: T-J
authors.initials: TJ
authors.lastname: Cai
authors.forename: X-Q
authors.initials: XQ
authors.lastname: Liu
authors.forename: M-C
authors.initials: MC
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Ke
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chen
authors.forename: W-J
authors.initials: WJ
authors.lastname: Luo
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002712:Chlorides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D017895:Manganese Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014446:Tyrosine 3-Monooxygenase; C025340:manganese chloride