MTF1 binds to metal‐responsive element e within the ATP7B promoter and is a strong candidate in regulating the ATP7B expression

Wilson's disease is an autosomal recessive disorder resulting from copper excess. Some patients with clinical Wilson's disease symptoms exhibit no or only heterozygous pathogenic variants in the coding region of the disease‐causing ATP7B gene. Therefore, the ATP7B promoter region is of spe...

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Bibliographic Details
Published in:Annals of human genetics 2020-03, Vol.84 (2), p.195-200
Main Authors: Stalke, Amelie, Pfister, Eva‐Doreen, Baumann, Ulrich, Illig, Thomas, Reischl, Eva, Sandbothe, Maria, Vajen, Beate, Huge, Nicole, Schlegelberger, Brigitte, von Neuhoff, Nils, Skawran, Britta
Format: Article
Language:English
Subjects:
ATP7B gene
Binding sites
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Copper-Transporting ATPases - genetics
Copper-Transporting ATPases - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Electrophoretic mobility
Gene expression
Gene Expression Regulation, Neoplastic
Hep G2 Cells
Hereditary diseases
Humans
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
metal regulatory transcription factor 1 (MTF1)
Metals - metabolism
metal‐responsive element (MRE)
Promoter Regions, Genetic
Regulatory sequences
Reporter gene
Response Elements
Transcription Factor MTF-1
Transcription Factors - genetics
Transcription Factors - metabolism
Wilson's disease
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Summary:Wilson's disease is an autosomal recessive disorder resulting from copper excess. Some patients with clinical Wilson's disease symptoms exhibit no or only heterozygous pathogenic variants in the coding region of the disease‐causing ATP7B gene. Therefore, the ATP7B promoter region is of special interest. Metal‐responsive elements (MREs) located in the ATP7B promoter are promising motifs in modulating the ATP7B expression. We studied protein interaction of MREe, MREc, and MREd by electrophoretic mobility shift assays and revealed specific interactions for all MREs. We further narrowed down the specific binding site. Proteins potentially binding to the three MREs were identified by MatInspector analyses. Metal regulatory transcription factor 1 (MTF1) could be validated to bind to MREe by electrophoretic mobility shift assays. ATP7B promoter‐driven reporter gene expression was significantly increased because of this interaction. MTF1 is a strong candidate in regulating the ATP7B expression through MREe binding.
ISSN:0003-4800
1469-1809
DOI:10.1111/ahg.12355