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Multiple Novel Alternative Splicing Forms of FBXW7α Have a Translational Modulatory Function and Show Specific Alteration in Human Cancer

Journal Article · · PLoS ONE
 [1];  [2];  [3];  [3];  [4];  [4];  [4];  [5];  [5];  [5];  [2];  [4]
  1. Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); DOE/OSTI
  2. Second Military Medical University, Shanghai (China)
  3. Instituto Mixto Universidad de Salamanca/CSIC, IBSAL, Campus, Salamanca (Spain)
  4. Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
  5. Hospital Universitario de Salamanca, IBSAL, Salamanca (Spain)
+ Show Author Affiliations
BXW7 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 59 region of FBXW7 gene to investigate the regulation of FBXW7 expression. We identified seven alternative splicing (AS) 59-UTR forms of FBXW7a that are composed of multiple novel non-coding exons. A significant difference in translational efficiency among these 59-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 FBXW7a AS forms with different translational properties may serve as a novel mechanism for inactivation of FBXW7 in human cancer.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
Ministry of Science & Technology of Shanghai; National Aeronautics and Space Administration (NASA); National Basic Research Program of China; National Institutes of Health; USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1627560
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 11 Vol. 7; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (3)

Guttiferone K impedes cell cycle re-entry of quiescent prostate cancer cells via stabilization of FBXW7 and subsequent c-MYC degradation journal June 2016
Epidermal Growth-Factor – Induced Transcript Isoform Variation Drives Mammary Cell Migration journal December 2013
FBXW7: a critical tumor suppressor of human cancers journal August 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
bladder cancer
breast cancer
gastrointestinal cancers
gene expression
luciferase
prostate cancer
renal cancer
reverse transcriptase-polymerase chain reaction