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Lead Neurotoxicity on Human Neuroblastoma Cell Line SH-SY5Y is Mediated via Transcription Factor EGR1/Zif268 Induced Disrupted in Scherophernia-1 Activation

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Abstract

Lead (Pb2+) is a well-known type of neurotoxin and chronic exposure to Pb2+ induces cognition dysfunction. In this work, the potential role of early growth response gene 1 (EGR1) in the linkage of Pb2+ exposure and disrupted in scherophernia-1 (DISC1) activity was investigated. Human neuroblastoma cell line SH-SY5Y was subjected to different concentrations of lead acetate (PbAc) to determine the effect of Pb2+ exposure on the cell viability, apoptosis, and activity of EGR1 and DISC1. Then the expression of EGR1 in SH-SY5Y cells was knocked down with specific siRNA to assess the function of EGR1 in Pb2+ induced activation of DISC1. The interaction between EGR1 and DISC1 was further validated with dual luciferase assay, Supershift electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP)-PCR. Administration of PbAc decreased cell viability and induced apoptosis in SH-SY5Y cells in a dose-dependent manner. Additionally, exposure to PbAc also up-regulated expression of EGR1 and DISC1 at all concentrations. Knockdown of EGR1 blocked the effect of PbAc on SH-SY5Y cells, indicating the central role of EGR1 in the function of Pb2+ on activity of DISC1. Based on the results of dual luciferase assay, Supershift EMSA, and ChIP-PCR, EGR1 mediated the effect of Pb2+ on DISC1 by directly bound to the promoter region of DISC1 gene. The current study elaborated the mechanism involved in the effect of Pb2+ exposure on expression of DISC1 for the first time: EGR1 activated by Pb2+ substitution of zinc triggered the transcription of DISC1 gene by directly binding to its promoter.

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The supporting data and materials reported in this manuscript are archived in the authors’ personal files. Researchers interested in accessing them should contact YYY or LGS.

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Author information

Authors and Affiliations

  1. Department of Genetic, Shenyang Maternity and Child Health Hospital, Shenyang, People’s Republic of China

    Yuanyuan You

  2. Outpatient Department, China Medical University, Shenyang, People’s Republic of China

    Bo Peng

  3. Life Science College, Liaoning University, Shenyang, People’s Republic of China

    Songbin Ben

  4. Department of Tissue Engineering, China Medical University, Shenyang, People’s Republic of China

    Weijian Hou

  5. Department of Biochemical and Molecular Biology, China Medical University, No. 77 of Puhe Road, Beixin District, Shenyang, 110127, Liaoning, People’s Republic of China

    Liguang Sun

  6. Department of Biological Science, Liaoning Academy of Analytical Sciences, Shenyang, People’s Republic of China

    Wei Jiang

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  1. Yuanyuan You
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  2. Bo Peng
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Contributions

SBB provided the predictive information; YYY and BP designed and conducted the experiments, YYY and SBB collected the data, WJH and WJ provided instruction during experiments; YYY and LGS analysis data separately; YYY completed the draft of manuscript; LGS revised manuscript draft; all authors confirmed the version before submitting.

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Correspondence to Liguang Sun.

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You, Y., Peng, B., Ben, S. et al. Lead Neurotoxicity on Human Neuroblastoma Cell Line SH-SY5Y is Mediated via Transcription Factor EGR1/Zif268 Induced Disrupted in Scherophernia-1 Activation. Neurochem Res 43, 1308–1316 (2018). https://doi.org/10.1007/s11064-018-2539-2

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  • DOI: https://doi.org/10.1007/s11064-018-2539-2

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