Genes and gene networks involved in sodium fluoride-elicited cell death accompanying endoplasmic reticulum stress in oral epithelial cells.
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.
Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. ytabu@cts.u-toyama.ac.jp.
Yoshiaki
Y
Tabuchi
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. yunokiki@med.u-toyama.ac.jp.
Tatsuya
T
Yunoki
Department of Animal Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai, Kobe 657-8501, Japan. nobhoshi@kobe-u.ac.jp.
Nobuhiko
N
Hoshi
Noto Marine Laboratory, Institute of Nature and Environmental Technology, Kanazawa University, Housu-gun, Ishikawa 927-0553, Japan. nobuos@staff.kanazawa-u.ac.jp.
Nobuo
N
Suzuki
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kondot@med.u-toyama.ac.jp.
Takashi
T
Kondo
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D016000:Cluster Analysis; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053263:Gene Regulatory Networks; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D012969:Sodium Fluoride / Q000633:toxicity*; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP
D051700:Activating Transcription Factor 3; D051701:Activating Transcription Factor 4; D053148:Caspase 3; D006360:Heat-Shock Proteins; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D012969:Sodium Fluoride; D051742:Transcription Factor CHOP; C497108:Atf3 protein, rat; C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP