Abstract
ABSTRACTOtitis 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.
Highlights
Otitis media with effusion (OME) is the commonest cause of hearing loss in children, and has effects on language development and learning, accompanied by behavioural problems
In this study, the authors examined the interaction between FBXO11, a member of the F-box family of proteins that is mutated in the Jeff mouse model, and p53, a putative substrate of FBX011
We studied in detail the genetic and biochemical interactions of Fbxo11 and p53 in developing mouse lungs, an organ that has similar properties to the middle ear (Takahashi, 2001) and for which we have previously demonstrated that FBXO11 has an important role in modulating TGF-β signalling
Summary
Otitis media with effusion (OME) is the commonest cause of hearing loss in children, and has effects on language development and learning, accompanied by behavioural problems. It is the most common cause of surgery for children in the developing world, involving the insertion of tympanostomy tubes. The Jf and Junbo mutants carry mutations in the Fbxo and Evi genes, respectively, and all three genes (Fbxo, Evi and Tgif1) impact upon TGF-β signalling. The development of COME in these mutants might reflect the interplay between TGF-β and hypoxia signalling pathways (Cheeseman et al, 2011). We investigated the occurrence of hypoxia and HIF-mediated responses in Junbo and Jf mutants, and showed cellular hypoxia in the white blood cells of both the middle-ear mucosa and middle-ear lumen (Cheeseman et al, 2011)
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