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Multiple novel alternative splicing forms of FBXW7α have a translational modulatory function and show specific alteration in human cancer.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (11), pp. e49453. Date of Electronic Publication: 2012 Nov 14. - Publication Year :
- 2012
-
Abstract
- FBXW7 acts as a tumor suppressor through ubiquitination and degradation of multiple oncoproteins. Loss of FBXW7 expression, which could be partially attributed by the genomic deletion or mutation of FBXW7 locus, is frequently observed in various human cancers. However, the mechanisms regulating FBXW7 expression still remain poorly understood. Here we examined the 5' region of FBXW7 gene to investigate the regulation of FBXW7 expression. We identified seven alternative splicing (AS) 5'-UTR forms of FBXW7α that are composed of multiple novel non-coding exons. A significant difference in translational efficiency among these 5'-UTRs variants was observed by in vivo Luciferase reporter assay and Western blot. Furthermore, we found that the mRNA level of the AS form with high translational efficiency was specifically reduced in more than 80% of breast cancer cell lines and in more than 50% of human primary cancers from various tissues. In addition, we also identified mutations of FBXW7 in prostate cancers (5.6%), kidney cancers (16.7%), and bladder cancers (18.8%). Our results suggest that in addition to mutation, differential expression of FBXW7α AS forms with different translational properties may serve as a novel mechanism for inactivation of FBXW7 in human cancer.
- Subjects :
- Analysis of Variance
Blotting, Western
Computational Biology
DNA Mutational Analysis
Exons genetics
F-Box-WD Repeat-Containing Protein 7
Gene Components
Gene Expression Profiling
Humans
Luciferases
RNA, Messenger genetics
Reverse Transcriptase Polymerase Chain Reaction
Alternative Splicing genetics
Cell Cycle Proteins genetics
F-Box Proteins genetics
Gene Expression Regulation, Neoplastic genetics
Neoplasms genetics
Protein Biosynthesis genetics
RNA, Messenger metabolism
Ubiquitin-Protein Ligases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23166673
- Full Text :
- https://doi.org/10.1371/journal.pone.0049453