title: Intermittent hypoxia-induced protein phosphatase 2A activation reduces PC12 cell proliferation and differentiation.
abstract: BACKGROUND
  Intermittent hypoxia (IH) plays a critical role in sleep breathing disorder-associated hippocampus impairments, including neurocognitive deficits, irreversible memory and learning impairments. IH-induced neuronal injury in the hippocampus may result from reduced precursor cell proliferation and the relative numbers of postmitotic differentiated neurons. However, the mechanisms underlying IH-induced reactive oxygen species (ROS) generation effects on cell proliferation and neuronal differentiation remain largely unknown.
  
  
  RESULTS
  ROS generation significantly increased after 1-4 days of IH without increased pheochromocytoma-12 (PC12) cell death, which resulted in increased protein phosphatase 2A (PP2A) mRNA and protein levels. After 3-4 days of IH, extracellular signal-regulated kinases 1/2 (ERK1/2) protein phosphorylation decreased, which could be reversed by superoxide dismutase (SOD), 1,10-phenanthroline (Phe), the PP2A phosphorylation inhibitors, okadaic acid (OKA) and cantharidin, and the ERK phosphorylation activator nicotine (p < 0.05). In particular, the significantly reduced cell proliferation and increased proportions of cells in the G0/G1 phase after 1-4 days of IH (p < 0.05), which resulted in decreased numbers of PC12 cells, could be reversed by treatment with SOD, Phe, PP2A inhibitors and an ERK activator. In addition, the numbers of nerve growth factor (NGF)-induced PC12 cells with neurite outgrowths after 3-4 days of IH were less than those after 4 days of RA, which was also reversed by SOD, Phe, PP2A inhibitors and an ERK activator.
  
  
  CONCLUSIONS
  Our results suggest that IH-induced ROS generation increases PP2A activation and subsequently downregulates ERK1/2 activation, which results in inhibition of PC12 cell proliferation through G0/G1 phase arrest and NGF-induced neuronal differentiation.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Chen
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Chiu
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Pan
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Hsu
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Lin
authors.affiliation: Master program, Physiology and Anatomical Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan. ktyang@mail.tcu.edu.tw.
authors.forename: Kun-Ta
authors.initials: KT
authors.lastname: Yang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000235:genetics*; D006624:Hippocampus / Q000201:enzymology; D000860:Hypoxia / Q000150:complications / Q000201:enzymology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D020932:Nerve Growth Factor; D013482:Superoxide Dismutase; D048052:Mitogen-Activated Protein Kinase 3; D054648:Protein Phosphatase 2