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Int. J. Mol. Sci. 2014, 15(5), 8959-8978; doi:10.3390/ijms15058959

Genes and Gene Networks Involved in Sodium Fluoride-Elicited Cell Death Accompanying Endoplasmic Reticulum Stress in Oral Epithelial Cells

1
Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
2
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
3
Department of Animal Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai, Kobe 657-8501, Japan
4
Noto Marine Laboratory, Institute of Nature and Environmental Technology, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan
*
Author to whom correspondence should be addressed.
Received: 13 February 2014 / Revised: 5 May 2014 / Accepted: 13 May 2014 / Published: 20 May 2014
(This article belongs to the Section Molecular Toxicology)
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Abstract

Here, to understand the molecular mechanisms underlying cell death induced by sodium fluoride (NaF), we analyzed gene expression patterns in rat oral epithelial ROE2 cells exposed to NaF using global-scale microarrays and bioinformatics tools. A relatively high concentration of NaF (2 mM) induced cell death concomitant with decreases in mitochondrial membrane potential, chromatin condensation and caspase-3 activation. Using 980 probe sets, we identified 432 up-regulated and 548 down-regulated genes, that were differentially expressed by >2.5-fold in the cells treated with 2 mM of NaF and categorized them into 4 groups by K-means clustering. Ingenuity® pathway analysis revealed several gene networks from gene clusters. The gene networks Up-I and Up-II included many up-regulated genes that were mainly associated with the biological function of induction or prevention of cell death, respectively, such as Atf3, Ddit3 and Fos (for Up-I) and Atf4 and Hspa5 (for Up-II). Interestingly, knockdown of Ddit3 and Hspa5 significantly increased and decreased the number of viable cells, respectively. Moreover, several endoplasmic reticulum (ER) stress-related genes including, Ddit3, Atf4 and Hapa5, were observed in these gene networks. These findings will provide further insight into the molecular mechanisms of NaF-induced cell death accompanying ER stress in oral epithelial cells. View Full-Text
Keywords: sodium fluoride; gene expression; gene network; cell death; endoplasmic reticulum stress; oral epithelial cell sodium fluoride; gene expression; gene network; cell death; endoplasmic reticulum stress; oral epithelial cell
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MDPI and ACS Style

Tabuchi, Y.; Yunoki, T.; Hoshi, N.; Suzuki, N.; Kondo, T. Genes and Gene Networks Involved in Sodium Fluoride-Elicited Cell Death Accompanying Endoplasmic Reticulum Stress in Oral Epithelial Cells. Int. J. Mol. Sci. 2014, 15, 8959-8978.

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