Truncation of the catalytic domain of the cylindromatosis tumor suppressor impairs lung maturation.
Cyld encodes a 956-amino acid deubiquitinating enzyme (CYLD), which is a negative regulator of nuclear factor kappaB and mitogen-activated protein kinase pathways. Mutations that truncate and inactivate the carboxyl-terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer. To establish an animal model of human CYLD inactivation and characterize the biological role of CYLD in vivo, we generated mice carrying a homozygous deletion of Cyld exon 9 (Cyld(Delta 9/Delta 9) mice) using a conditional approach. Deletion of exon 9 would cause a carboxyl-terminal truncation of CYLD and inactivation of its deubiquitinating activity. In accordance with previous studies, fibroblasts from Cyld(Delta 9/Delta 9) embryos had hyperactive nuclear factor kappaB and c-Jun kinase pathways compared with control fibroblasts. Cyld(Delta 9/Delta 9) newborn mice were smaller than wild-type littermates with a short and kinky tail and no major developmental defects. However, Cyld(Delta 9/Delta 9) mice died shortly after birth from apparent respiratory dysfunction. Histological examination of E18.5 Cyld(Delta 9/Delta 9) lungs demonstrated an immature phenotype characterized by hyperplasic mesenchyme but apparently normal epithelial, smooth muscle. and endothelial structures. Our study identifies an important role of CYLD in lung maturation, which may underlie the development of many cases of lung cancer.
Institute of Immunology, Biomedical Sciences Research Center Al. Fleming, 34 Al. Fleming Str, Vari 16672, Greece.
Eirini
E
Trompouki
Ageliki
A
Tsagaratou
Stylianos K
SK
Kosmidis
Pascal
P
Dollé
Jun
J
Qian
Dimitris L
DL
Kontoyiannis
Wellington V
WV
Cardoso
George
G
Mosialos
D000818:Animals; D020134:Catalytic Domain; D002465:Cell Movement / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D005347:Fibroblasts / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008168:Lung / Q000196:embryology* / Q000254:growth & development*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism
D016328:NF-kappa B; D048670:MAP Kinase Kinase 4; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases