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The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells

1
Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
2
Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432–1, Horinouchi, Hachioji, Tokyo 192–0392, Japan
3
Laboratory of Pharmaceutical Health Sciences, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan
*
Author to whom correspondence should be addressed.
Cells 2020, 9(1), 45; https://doi.org/10.3390/cells9010045
Received: 12 November 2019 / Revised: 20 December 2019 / Accepted: 21 December 2019 / Published: 23 December 2019
Homeobox protein B13 (HOXB13), a transcription factor, is related to methylmercury toxicity; however, the downstream factors involved in enhancing methylmercury toxicity remain unknown. We performed microarray analysis to search for downstream factors whose expression is induced by methylmercury via HOXB13 in human embryonic kidney cells (HEK293), which are useful model cells for analyzing molecular mechanisms. Methylmercury induced the expression of oncostatin M (OSM), a cytokine of the interleukin-6 family, and this was markedly suppressed by HOXB13 knockdown. OSM knockdown also conferred resistance to methylmercury in HEK293 cells, and no added methylmercury resistance was observed when both HOXB13 and OSM were knocked down. Binding of HOXB13 to the OSM gene promoter was increased by methylmercury, indicating the involvement of HOXB13 in the enhancement of its toxicity. Because addition of recombinant OSM to the medium enhanced methylmercury toxicity in OSM-knockdown cells, extracellularly released OSM was believed to enhance methylmercury toxicity via membrane receptors. We discovered tumor necrosis factor receptor (TNF) receptor 3 (TNFR3) to be a potential candidate involved in the enhancement of methylmercury toxicity by OSM. This toxicity mechanism was also confirmed in mouse neuronal stem cells. We report, for the first time, that HOXB13 is involved in enhancement of methylmercury toxicity via OSM-expression induction and that the synthesized OSM causes cell death by binding to TNFR3 extracellularly. View Full-Text
Keywords: methylmercury; HOXB13; oncostatin M; TNF receptor 3 methylmercury; HOXB13; oncostatin M; TNF receptor 3
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MDPI and ACS Style

Toyama, T.; Xu, S.; Nakano, R.; Hasegawa, T.; Endo, N.; Takahashi, T.; Lee, J.-Y.; Naganuma, A.; Hwang, G.-W. The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells. Cells 2020, 9, 45. https://doi.org/10.3390/cells9010045

AMA Style

Toyama T, Xu S, Nakano R, Hasegawa T, Endo N, Takahashi T, Lee J-Y, Naganuma A, Hwang G-W. The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells. Cells. 2020; 9(1):45. https://doi.org/10.3390/cells9010045

Chicago/Turabian Style

Toyama, Takashi, Sidi Xu, Ryo Nakano, Takashi Hasegawa, Naoki Endo, Tsutomu Takahashi, Jin-Yong Lee, Akira Naganuma, and Gi-Wook Hwang. 2020. "The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells" Cells 9, no. 1: 45. https://doi.org/10.3390/cells9010045

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