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Abortive Cell Cycle Events in the Brains of Scrapie-Infected Hamsters with Remarkable Decreases of PLK3/Cdc25C and Increases of PLK1/Cyclin B1

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Abstract

Polo-like kinases (PLKs) consist of a family of kinases which play critical roles during multiple stages of cell cycle progression. Increase of PLK1 and decrease of PLK3 are associated with the developments and metastases of many types of human malignant tumors; however, the situations of PLKs in prion diseases are less understood. Using Western blots and immunohistochemical and immunofluorescent assays, marked increase of PLK1 and decrease of PLK3 were observed in the brains of scrapie strain 263K-infected hamsters, presenting obviously a time-dependent phenomenon along with disease progression. Similar alterations of PLKs were also detected in a scrapie infectious cell line SMB-S15. Both PLK1 and PLK3 were observed in neurons by confocal microscopy. Accompanying with the changes of PLKs in the brains of 263K-infected hamsters, Cdc25C and its phosphorylated forms (p-Cdc25C-Ser198 and p-Cdc25C-Ser216) were significantly down-regulated, whereas Cyclin B1 and PCNA were obviously up-regulated, while phospho-histone H3 remained almost unchanged. Moreover, exposure of the cytotoxic peptide PrP106-126 on the primary cultured cortical neuron cells induced similar changes of cellular PLKs and some cell cycle-related proteins, such as Cdc25C and its phosphorylated forms, phospho-histone H3. Those results illustrate obviously aberrant expressions of cell cycle regulatory proteins in the prion-infected neurons, which may lead to the cell cycle arrest at M phase. Possibly due to the ill-regulation of some key cell cycle events during prion infection, together with the fact that neurons are unable to complete mitosis, the cell cycle reentry in prion-infected neurons is definitely abortive, which may lead to neuron apoptosis and neuron degeneration.

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Acknowledgments

This work was supported by the Chinese National Natural Science Foundation Grant (81101302, 81273202), China Mega-Project for Infectious Disease (2011ZX10004-101, 2012ZX10004215), SKLID Development Grant (2012SKLID102), and Sci-tech Innovation Team of Jiangsu University (2008-018-02). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Immunology, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, 212013,, Jiangsu, China

    Hui Wang & Qi-Xiang Shao

  2. State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing, 102206, China

    Hui Wang, Chan Tian, Yin Xu, Wu-Ling Xie, Jin Zhang, Bao-Yun Zhang, Ke Ren, Ke Wang, Cao Chen, Shao-Bin Wang, Qi Shi & Xiao-Ping Dong

  3. School of Medicine, Xi’an Jiao Tong University, Xi’an, 710061, Shaanxi, China

    Wu-Ling Xie & Ke Wang

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Hui Wang and Chan Tian contributed equally to this article.

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Supplemental Fig. 1

NeuN-specific IFA of the primary cultured rat cortical neurons. The images of NeuN (red), DAPI (blue) and merge are indicated above (PDF 42 kb)

Supplemental Fig. 2

Western blots of Cyclin the lysates of the cell line SMB-S15 and SMB-PS (left). Quantitative analyses of the gray numerical values of the blots vs. that of the individual β-actin are showed on the right. The average relative gray value is calculated from three independent blots and presented as mean ± SEM. **p<0.001 significant compared to controls are illustrated on the top (PDF 106 kb)

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Wang, H., Tian, C., Xu, Y. et al. Abortive Cell Cycle Events in the Brains of Scrapie-Infected Hamsters with Remarkable Decreases of PLK3/Cdc25C and Increases of PLK1/Cyclin B1. Mol Neurobiol 48, 655–668 (2013). https://doi.org/10.1007/s12035-013-8455-1

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