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Regulation of SET Gene Expression by NFkB

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Abstract

SET is elevated and mislocalized in the neuronal cytoplasm in brains of Alzheimer’s disease (AD) and Down syndrome (DS) patients. Cytoplasm SET leads to inhibition of protein phosphatase 2A and is involved in the tau pathology. However, the regulation of SET gene expression remains elusive. In the present study, we cloned a 1399-bp segment of the 5′ flanking region of the human SET gene and identified that the transcription start site (TSS) of SET transcript 1 is located at 123 bp upstream of the translation start site ATG in exon 1. Sequence analysis reveals several putative regulatory elements including NFkB, Sp1, and HSE. Luciferase assay and electrophoretic mobility shift assay (EMSA) identified a functional cis-acting NFkB-responsive element in the SET gene promoter. Overexpression and activation of NFkB upregulate transcription of SET isoform 1 but not isoform 2, indicating that the expression of these two isoforms is differentially regulated. The results demonstrate that NFkB plays an important role in regulation of the human SET gene expression. Our findings suggest that oxidative stress and inflammatory responses could result in abnormal SET gene expression, contributing to the tauopathy in AD pathogenesis.

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Acknowledgments

We thank Shasha Meng and Mingjing Liu for providing valuable comments and technique support. This work was supported by the Graduate Student Research Innovation Project of Chongqing, National Natural Science Foundation of China (NSFC) grant 81161120498 (T. L.), and Canadian Institutes of Health Research (CIHR) Grant TAD-117948 (W.S.). W.S. is the holder of the Tier 1 Canada Research Chair in Alzheimer’s disease.

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    Authors and Affiliations

    1. Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders and Ministry of Education Key Lab of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

      Yi Feng, Xiaoyong Li, Weitao Zhou, Dandan Lou, Daochao Huang, Yanhua Li, Yu Kang, Yan Xiang, Tingyu Li, Weihui Zhou & Weihong Song

    2. Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

      Weihong Song

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    Yi Feng, Xiaoyong Li and Weitao Zhou contributed equally to this work.

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    Feng, Y., Li, X., Zhou, W. et al. Regulation of SET Gene Expression by NFkB. Mol Neurobiol 54, 4477–4485 (2017). https://doi.org/10.1007/s12035-016-9967-2

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