Truncation of the catalytic domain of the cylindromatosis tumor suppressor impairs lung maturation

Eirini Trompouki, Ageliki Tsagaratou, Stylianos K Kosmidis, Pascal Dolle, Jun Qian, Dimitris L Kontoyiannis, Wellington V. Cardoso and George Mosialos

Year 2009, Volume 11, Issue 5

Abstract

Cyld encodes a 956 amino acid deubiquitinating enzyme (CYLD) which is a negative regulator of NF-kappaB and MAP kinase pathways. Mutations that truncate and inactivate the carboxyl terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas downregulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer. In order 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ハDelta9/Delta9 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ハDelta9/Delta9 embryos had hyperactive NF-kappaB and JNK pathways compared to control fibroblasts. CyldハDelta9/Delta9 mice were smaller than wild type littermates with a short and kinky tail and no major developmental defects. However, CyldハDelta9/Delta9 mice died shortly after birth from apparent respiratory dysfunction. Histological examination of E18.5 CyldハDelta9/Delta9 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.

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