Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Increased expression of TCF3, transcription factor 3, is a defense response against methylmercury toxicity in mouse neuronal C17.2 cells

  • Toyama, Takashi (Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Wang, Yanjiao (Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Kim, Min-Seok (Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Takahashi, Tsutomu (Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Naganuma, Akira (Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Hwang, Gi-Wook (Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University)
  • Received : 2020.12.17
  • Accepted : 2021.01.06
  • Published : 2021.10.15
⟨ Previous Next ⟩

Abstract

Methylmercury is an environmental pollutant that induces potent neurotoxicity. We previously identified transcription factor 3 (TCF3) as a transcription factor that is activated in the brains of mice treated with methylmercury, and reported that methylmercury sensitivity was increased in cells in which TCF3 expression was suppressed. However, the mechanisms involved in the activation of TCF3 by methylmercury and in the reduction of methylmercury toxicity by TCF3 remained unclear. We found that treatment of mouse neuronal C17.2 cells with methylmercury increased TCF3 protein levels and promoted the binding of TCF3 to DNA consensus sequences. In cells treated with actinomycin D, a transcription inhibitor, an increase in TCF3 protein levels was also observed under methylmercury exposure. However, in the presence of cycloheximide, a translation inhibitor, methylmercury delayed the degradation of TCF3 protein. In addition, treatment with MG132, a proteasome inhibitor, increased TCF3 protein levels, and there was not significant increase in TCF3 protein levels by methylmercury under these conditions. These results suggest that methylmercury may activate TCF3 by increasing its levels through inhibition of TCF3 degradation by the proteasome. It has been previously reported that the induction of apoptosis in neurons is involved in methylmercury-induced neuronal damage in the brain. Although apoptosis was induced in C17.2 cells treated with methylmercury, this induction was largely suppressed by overexpression of TCF3. These results indicate that TCF3, which is increased in the brain upon exposure to methylmercury, may be a novel defense factor against methylmercury-induced neurotoxicity.

Keywords

Acknowledgement

This work was partially supported by JSPS KAK-ENHI Grant Number 15H05714 and 19H04276. We thank Emma Longworth-Mills, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

References

  1. Antunes DSA, Appel HM, Culbreth M, Lopez-Granero C, Farina M, Rocha JB, Aschner M (2016) Methylmercury and brain development: a review of recent literature. J Trace Elem Med Biol 38:99-107. https://doi.org/10.1016/j.jtemb.2016.03.001
  2. Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N (2002) Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem J 367:239-246. https://doi.org/10.1042/BJ20020841
  3. Harada M (1995) Minamata disease: methylmercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol 25:1-24. https://doi.org/10.3109/10408449509089885
  4. Harada M (1978) Congenital minamata disease: intrauterine methylmercury poisoning. Teratology 18:285-288. https://doi.org/10.1002/tera.1420180216
  5. Unoki T, Abiko Y, Toyama T, Uehara T, Tsuboi K, Nishida M, Kaji T, Kumagai Y (2016) Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells. Sci Rep 6:28944. https://doi.org/10.1038/srep28944
  6. Toyama T, Sumi D, Shinkai Y, Yasutake A, Taguchi K, Tong KI, Yamamoto M, Kumagai Y (2007) Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity. Biochem Biophys Res Commun 363:645-650. https://doi.org/10.1016/j.bbrc.2007.09.017
  7. Toyama T, Shinkai Y, Yasutake A, Uchida K, Yamamoto M, Kumagai Y (2011) Isothiocyanates reduce mercury accumulation via an Nrf2-dependent mechanism during exposure of mice to methylmercury. Environ Health Perspect 119:1117-1122. https://doi.org/10.1289/ehp.1003123
  8. Hwang GW, Ryoke K, Lee JY, Takahashi T, Naganuma A (2011) siRNA-mediated silencing of the gene for heat shock transcription factor 1 causes hypersensitivity to methylmercury in HEK293 cells. J Toxicol Sci 36:851-853. https://doi.org/10.2131/jts.36.851
  9. ToyamaT XS, Nakano R, Hasegawa T, Endo N, Takahashi T, Lee JY, Naganuma A, Hwang GW (2020) The nuclear protein HOXB13 enhances methylmercury toxicity by inducing oncostatin M and promoting its binding to TNFR3 in cultured cells. Cells 9:45. https://doi.org/10.3390/cells9010045
  10. Iwai-Shimada M, Takahashi T, Kim MS, Fujimura M, Ito H, Toyama T, Naganuma A, Hwang GW (2016) Methylmercury induces the expression of TNF-alpha selectively in the brain of mice. Sci Rep 6:38294. https://doi.org/10.1038/srep38294
  11. Gribble EJ, Hong SW, Faustman EM (2005) The magnitude of methylmercury-induced cytotoxicity and cell cycle arrest is p53-dependent. Birth Defects Res A 73:29-38. https://doi.org/10.1002/bdra.20104
  12. Takahashi T, Yanjiao W, Toyama T, Kim MS, Kuge S, Hwang GW, Naganuma A (2017) Small interfering RNA-mediated knockdown of the transcription factor TCF3 enhances sensitivity to methylmercury in mouse neural stem cells. Fundam Toxicol Sci 4:41-43. https://doi.org/10.2131/fts.4.41
  13. Patel D, Chinaranagari S, Chaudhary J (2015) Basic helix loop helix (bHLH) transcription factor 3 (TCF3, E2A) is regulated by androgens in prostate cancer cells. Am J Cancer Res 5:3407-3421. PMID: 26807321
  14. Hashimoto Y, Tsutsumi M, Myojin R, Maruta K, Onoda F, Tashiro F, Ohtsu M, Murakami Y (2011) Interaction of Hand2 and E2a is important for transcription of Phox2b in sympathetic nervous system neuron differentiation. Biochem Biophys Res Commun 408:38-44. https://doi.org/10.1016/j.bbrc.2011.03.113
  15. Patel D, Chaudhary J (2012) Increased expression of bHLH transcription factor E2A (TCF3) in prostate cancer promotes proliferation and confers resistance to doxorubicin induced apoptosis. Biochem Biophys Res Commun 422:146-151. https://doi.org/10.1016/j.bbrc.2012.04.126
  16. Andrysik Z, Kim J, Tan AC, Espinosa JM (2013) A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation. Cell Rep 3:1346-1354. https://doi.org/10.1016/j.celrep.2013.04.014
  17. Loveys DA, Streiff MB, Schaefer TS, Kato GJ (1997) The mUBC9 murine ubiquitin conjugating enzyme interacts with the E2A transcription factors. Gene 201:169-177. https://doi.org/10.1016/S0378-1119(97)00444-7
  18. Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M (2001) Induction of HIF-1 alpha in response to hypoxia is instantaneous. FASEB J 15:1312-1314 https://doi.org/10.1096/fj.00-0732fje
  19. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O'Connor T, Yamamoto M (2003) Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8:379-391. https://doi.org/10.1046/j.1365-2443.2003.00640.x
  20. Loveys DA, Streiff MB, Kato GJ (1996) E2A basic-helix-loop-helix transcription factors are negatively regulated by serum growth factors and by the Id3 protein. Nucl Acid Res 24:2813-2820. https://doi.org/10.1093/nar/24.14.2813
  21. Kurooka H, Sugai M, Mori K, Yokota Y (2013) The metalloid arsenite induces nuclear export of Id3 possibly via binding to the N-terminal cysteine residues. Biochem Biophys Res Commun 433:579-585. https://doi.org/10.1016/j.bbrc.2013.03.027
  22. Qiu W, Wang XW, Leibowitz B, Yang WC, Zhang L, Yu J (2011) PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice. Hepatology 54:1249-1258. https://doi.org/10.1002/hep.24516
  23. Usuki F, Fujita E, Sasagawa N (2008) Methylmercury activates ASK1/JNK signaling pathways, leading to apoptosis due to both mitochondria- and endoplasmic reticulum (ER)-generated processes in myogenic cell lines. Neurotoxicology 29:22-30. https://doi.org/10.1016/j.neuro.2007.08.011
  24. Makino K, Okuda K, Sugino E, Nishiya T, Toyama T, Iwawaki T, Fujimura M, Kumagai Y, Uehara T (2015) Correlation between attenuation of protein disulfide isomerase activity through S-mercuration and neurotoxicity induced by methylmercury. Neurotox Res 27:99-105. https://doi.org/10.1007/s12640-014-9494-8

Cited by

  1. Knockdown of deubiquitinating enzyme Usp34 confers resistance to methylmercury in HEK293 cells vol.8, pp.5, 2021, https://doi.org/10.2131/fts.8.157