Intermittent hypoxia-induced protein phosphatase 2A activation reduces PC12 cell proliferation and differentiation

Journal of Biomedical Science

Kun-Ta Yang²  Jian-Hong Lin⁵  Shih-Ting Hsu³  Yi-Chung Pan⁴  Hung-Wen Chiu⁴  Tsung-I Chen¹ 

[1] Center of Physical Education, Office of General and Basic Education, Tzu Chi University, Hualien, Taiwan;Department of Physiology, College of Medicine, Tzu Chi University, No.701, Sec. 3, Chung-Yang Rd, Hualien 97004, Taiwan;Department of Life Science, Tzu Chi University, Hualien, Taiwan;Master program, Physiology and Anatomical Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan;PhD program in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien, Taiwan

关键词: Neurite outgrowth;    Cell cycle;    Cell viability;    Apoptosis;    Oxidative stress;   

Others  :  817534
DOI  :  10.1186/1423-0127-21-46

 received in 2013-08-06, accepted in 2013-11-26,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Chen et al.; licensee BioMed Central Ltd.

【 图 表 】

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