A somatic mutation in the 5'UTR of BRCA1 gene in sporadic breast cancer causes down-modulation of translation efficiency.

Détails

ID Serval
serval:BIB_93F33A8E7C3C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
A somatic mutation in the 5'UTR of BRCA1 gene in sporadic breast cancer causes down-modulation of translation efficiency.
Périodique
Oncogene
Auteur(s)
Signori E., Bagni C., Papa S., Primerano B., Rinaldi M., Amaldi F., Fazio V.M.
ISSN
0950-9232 (Print)
ISSN-L
0950-9232
Statut éditorial
Publié
Date de publication
27/07/2001
Volume
20
Numéro
33
Pages
4596-4600
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Mutations in the 5' UTR which cause increment/decrement of translation efficiency have been recently described as a novel molecular mechanism of disease. Alterations in the consensus sequence for the translation initiation may promote context-dependent leaky scanning of ribosomes and/or initiation from a downstream AUG codon. Initiation of translation from a downstream in-frame AUG codon in BRCA1 gene was recently identified in normal cells and possibly in breast cancer. Here we present further insight into BRCA1 translational pathophysiology investigating the role of the canonical structure of the initiation consensus sequence of BRCA1. We have analysed the effect of a somatic point mutation (117 G>C) in position -3 with respect to the AUG of the BRCA1 gene, identified in a highly aggressive sporadic breast cancer. We constructed chimeric genes encoding the luciferase reporter sequence downstream of the wild type or the mutated BRCA1 5'UTR. These transcripts were tested for their activity in in vitro and in vivo systems. In in vitro transcription/translation assays the estimated translation efficiency of the construct with the mutated BRCA1 5'UTR was 30-50% lower than that with the wild type BRCA1 5'UTR. The same chimeric genes were analysed for their expression in vivo by transient transfection in human cells. While the two constructs were equally transcribed, the plasmid carrying the mutated sequence produced 70% less luciferase activity compared to the wild type sequence. Finally, to obtain a direct evaluation on translational efficiency in vivo, we analysed mRNA translation on translationally active and non-active ribosomes separated from transfected cells. Mutant mRNA was partially localized in subpolysomal particles analytically confirming a polysome recruitment defect. Thus, characterization of BRCA1 5'UTR and translation efficiency seems to provide new insight into BRCA1 role in breast and ovarian cancer pathogenesis.

Mots-clé
5' Untranslated Regions/genetics, Bacteriophage T7/genetics, Breast Neoplasms/genetics, Carcinoma/genetics, Cell Line, Cell-Free System, Consensus Sequence, Female, Genes, BRCA1, Genes, Reporter, Genes, Synthetic, Humans, Kidney, Luciferases/biosynthesis, Luciferases/genetics, Mutation, Peptide Chain Initiation, Translational/genetics, Promoter Regions, Genetic, Protein Biosynthesis, Recombinant Fusion Proteins/biosynthesis, Recombinant Fusion Proteins/genetics
Pubmed
Open Access
Oui
Création de la notice
06/03/2017 18:23
Dernière modification de la notice
08/05/2019 22:12
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