Classification of a frameshift/extended and a stop mutation in WT1 as gain-of-function mutations that activate cell cycle genes and promote Wilms tumour cell proliferation
| العنوان: | Classification of a frameshift/extended and a stop mutation in WT1 as gain-of-function mutations that activate cell cycle genes and promote Wilms tumour cell proliferation |
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| المؤلفون: | Hans-Dieter Royer, Nicole Görldt, Brigitte Royer-Pokora, Paul J. Romaniuk, Stefan G. E. Roberts, Maike Busch, Manfred Beier, Artur Brandt, Heinrich Schwindt, Eneda Toska |
| المصدر: | Human Molecular Genetics |
| بيانات النشر: | Oxford University Press (OUP), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | congenital, hereditary, and neonatal diseases and abnormalities, Primary Cell Culture, Mutant, Biology, urologic and male genital diseases, medicine.disease_cause, Wilms Tumor, Frameshift mutation, Cell Line, Tumor, Protein Interaction Mapping, Genetics, medicine, Humans, Protein Isoforms, Gene Regulatory Networks, WT1 Proteins, Molecular Biology, Genetics (clinical), Cell Proliferation, Regulation of gene expression, Gene knockdown, Mutation, urogenital system, Gene Expression Profiling, Cell Cycle, fungi, Mesenchymal Stem Cells, Molecular Sequence Annotation, Wilms' tumor, Articles, General Medicine, Cell cycle, medicine.disease, Cell Cycle Gene, female genital diseases and pregnancy complications, 3. Good health, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Cancer research, Tumor Suppressor Protein p53 |
| الوصف: | The WT1 gene encodes a zinc finger transcription factor important for normal kidney development. WT1 is a suppressor for Wilms tumour development and an oncogene for diverse malignant tumours. We recently established cell lines from primary Wilms tumours with different WT1 mutations. To investigate the function of mutant WT1 proteins, we performed WT1 knockdown experiments in cell lines with a frameshift/extension (p.V432fsX87 = Wilms3) and a stop mutation (p.P362X = Wilms2) of WT1, followed by genome-wide gene expression analysis. We also expressed wild-type and mutant WT1 proteins in human mesenchymal stem cells and established gene expression profiles. A detailed analysis of gene expression data enabled us to classify the WT1 mutations as gain-of-function mutations. The mutant WT1(Wilms2) and WT1(Wilms3) proteins acquired an ability to modulate the expression of a highly significant number of genes from the G2/M phase of the cell cycle, and WT1 knockdown experiments showed that they are required for Wilms tumour cell proliferation. p53 negatively regulates the activity of a large number of these genes that are also part of a core proliferation cluster in diverse human cancers. Our data strongly suggest that mutant WT1 proteins facilitate expression of these cell cycle genes by antagonizing transcriptional repression mediated by p53. We show that mutant WT1 can physically interact with p53. Together the findings show for the first time that mutant WT1 proteins have a gain-of-function and act as oncogenes for Wilms tumour development by regulating Wilms tumour cell proliferation. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7b8f17e9fc40bd4015035ddc1d69f4e7Test https://doi.org/10.1093/hmg/ddu111Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7b8f17e9fc40bd4015035ddc1d69f4e7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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