title: Multiple novel alternative splicing forms of FBXW7α have a translational modulatory function and show specific alteration in human cancer.
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.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Yueyong
authors.initials: Y
authors.lastname: Liu
authors.forename: Shancheng
authors.initials: S
authors.lastname: Ren
authors.forename: Andres
authors.initials: A
authors.lastname: Castellanos-Martin
authors.forename: Jesus
authors.initials: J
authors.lastname: Perez-Losada
authors.forename: Yong-Won
authors.initials: YW
authors.lastname: Kwon
authors.forename: Yurong
authors.initials: Y
authors.lastname: Huang
authors.forename: Zeran
authors.initials: Z
authors.lastname: Wang
authors.forename: Mar
authors.initials: M
authors.lastname: Abad
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cruz-Hernandez
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Rodriguez
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Sun
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000704:Analysis of Variance; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics*; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D040461:Gene Components; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008156:Luciferases; D009369:Neoplasms / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D012333:RNA, Messenger; D008156:Luciferases; D044767:Ubiquitin-Protein Ligases