Interactions between the otitis media gene, Fbxo11, and p53 in the mouse embryonic lung
File(s)
Published version
Accepted version
Author(s)
Tateossian, H
Morse, S
Simon, MM
Dean, CH
Brown, SDM
Type
Journal Article
Abstract
Otitis media with effusion (OME) is the most common cause of hearing loss in children, and tympanostomy (ear tube insertion) to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of otitis media (OM) are known to have a very substantial genetic component; however, until recently, little was known of the underlying genes involved. The Jeff mouse mutant carries a mutation in the Fbxo11 gene, a member of the F-box family, and develops deafness due to a chronic proliferative OM. We previously reported that Fbxo11 is involved in the regulation of transforming growth factor beta (TGF-β) signalling by regulating the levels of phospho-Smad2 in the epithelial cells of palatal shelves, eyelids and airways of the lungs. It has been proposed that FBXO11 regulates the cell's response to TGF-β through the ubiquitination of CDT2. Additional substrates for FBXO11 have been identified, including p53. Here, we have studied both the genetic and biochemical interactions between FBXO11 and p53 in order to better understand the function of FBXO11 in epithelial development and its potential role in OM. In mice, we show that p53 (also known as Tp53) homozygous mutants and double heterozygous mutants (Jf/+ p53/+) exhibit similar epithelial developmental defects to Fbxo11 homozygotes. FBXO11 and p53 interact in the embryonic lung, and mutation in Fbxo11 prevents the interaction with p53. Both p53 and double mutants show raised levels of pSMAD2, recapitulating that seen in Fbxo11 homozygotes. Overall, our results support the conclusion that FBXO11 regulates the TGF-β pathway in the embryonic lung via cross-talk with p53.
Date Issued
2015-10-15
Date Acceptance
2015-10-12
Citation
Disease Models & Mechanisms, 2015, 8 (12), pp.1531-1542
ISSN
1754-8411
Publisher
Company of Biologists
Start Page
1531
End Page
1542
Journal / Book Title
Disease Models & Mechanisms
Volume
8
Issue
12
Copyright Statement
© 2015. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
Pathology
Otitis media
FBXO11
p53
TGF-beta
Lung
GROWTH-FACTOR-BETA
GENOME-WIDE ASSOCIATION
TGF-BETA
TRANSCRIPTIONAL ACTIVITY
BRANCHING MORPHOGENESIS
SUSCEPTIBILITY LOCI
CELLULAR MIGRATION
SPONTANEOUS TUMORS
UBIQUITIN LIGASE
EFFUSION
TGF-β
Developmental Biology
06 Biological Sciences
11 Medical And Health Sciences
Publication Status
Published