Cancer gene therapy, 2010-11, Vol.17 (11), p.814-825
2010
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- Autor(en) / Beteiligte
- Titel
- Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients
- Ist Teil von
- Cancer gene therapy, 2010-11, Vol.17 (11), p.814-825
- Ort / Verlag
- New York: Nature Publishing Group US
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the occurrence of tumors of parathyroids, neuroendocrine cells of the gastro-enteropancreatic tract and anterior pituitary. MEN1 gene encodes menin-oncosuppressor protein. Loss of heterozygosity at 11q13 is typical of MEN1 tumors. We have analyzed the MEN1 mRNA and menin expression in fibroblasts from normal skin biopsies and from MEN1 patients (two with a frameshift 738del4 (exon 3) mutation, introducing a premature stop codon, and an individual with an R460X (exon 10) nonsense mutation). The expression of full-length menin protein did not differ between MEN1 and normal fibroblasts. Wild-type alleles mRNAs were expressed in MEN1 patients, whereas mutant alleles were partially degraded by nonsense-mediated mRNA decay pathway, suggesting a mechanism of compensation for allelic loss by the up-regulation of wild-type menin expression at a post-transcriptional level. Small-interfering RNA silencing of the wild-type mRNA allele abolished menin compensation, whereas the ribozyme silencing of the MEN1- mutated mRNA allele resulted in strongly enhanced wild-type menin expression. Gel-retardation analysis showed that in vitro- specific RNA–protein complexes bound to MEN1 mRNA. These findings contribute to the understanding of tumorigenesis in MEN1, offering the basis for the development of RNA-based therapies in MEN1 gene mutation carriers.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0929-1903eISSN: 1476-5500DOI: 10.1038/cgt.2010.39Titel-ID: cdi_proquest_miscellaneous_874180272
- Format
- –
- Schlagworte
- 631/208/737, 631/337/176/2016, 692/699/67/1459, Adult, Alleles, Analysis, Anopheles, Biomedical and Life Sciences, Biomedicine, Biopsy, Caspase 8 - metabolism, Catalytic RNA, Exons, Female, Fibroblasts, Fibroblasts - metabolism, Frameshift mutation, Gene Expression, Gene Expression Regulation, Neoplastic, Gene mutations, Gene Therapy, Health aspects, Heterozygosity, Humans, Loss of Heterozygosity, Male, Middle Aged, mRNA turnover, Multiple endocrine neoplasia, Multiple Endocrine Neoplasia Type 1 - genetics, Multiple Endocrine Neoplasia Type 1 - metabolism, Mutation, Neuroendocrine tumors, Nonsense mutation, Nonsense-mediated mRNA decay, original-article, Pituitary (anterior), Point mutation, Post-transcription, Proteins, Proto-Oncogene Proteins - genetics, Proto-Oncogene Proteins - metabolism, RNA Interference, RNA, Catalytic - metabolism, RNA, Messenger - metabolism, RNA, Small Interfering - metabolism, RNA-mediated interference, siRNA, Somatic cells, Stop codon, Tumor Cells, Cultured, Tumorigenesis, Up-Regulation