title: Regulation of SET Gene Expression by NFkB.
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.
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Weitao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Dandan
authors.initials: D
authors.lastname: Lou
authors.affiliation: 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.
authors.forename: Daochao
authors.initials: D
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: 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. tyli@vip.sina.com.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Li
authors.affiliation: 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. zwh@cqmu.edu.cn.
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 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. weihong@mail.ubc.ca.|Townsend Family Laboratories, Department of Psychiatry, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. weihong@mail.ubc.ca.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056488:Histone Chaperones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D016328:NF-kappa B; D020033:Protein Isoforms; C513473:SET protein, human; D014157:Transcription Factors
keywords: Alzheimer’s disease; NFkB; SET; Sp1; Transcription