Abstract
The human cylindromatosis tumor suppressor (HsCyld) has attracted extensive attention due to its association with the development of multiple types of cancer. HsCyld encodes a deubiquitinating enzyme (HsCYLD) with a broad range of functions that include the regulation of several cell growth, differentiation and death pathways. HsCyld is an evolutionarily conserved gene. Homologs of HsCyld have been identified in simple model organisms such as Drosophila melanogaster and Caenorhabditis elegans (C. elegans) which offer extensive possibilities for functional analyses. In the present report we have investigated and compared the functional properties of HsCYLD and its C. elegans homolog (CeCYLD). As expected from the mammalian CYLD expression pattern, the CeCyld promoter is active in multiple tissues with certain gastrointestinal epithelia and neuronal cells showing the most prominent activity. CeCYLD is a functional deubiquitinating enzyme with similar specificity to HsCYLD towards K63- and M1-linked polyubiquiting chains. CeCYLD was capable of suppressing the TRAF2-mediated activation of NF-kappaB and AP1 similarly to HsCYLD. Finally, CeCYLD could suppress the induction of TNF-dependent gene expression in mammalian cells similarly to HsCYLD. Our results demonstrate extensively overlapping functions between the HsCYLD and CeCYLD, which establish the C. elegans protein as a valuable model for the elucidation of the complex activity of the human tumor suppressor protein.
Highlights
Inactivating mutations in the human Cyld gene (HsCyld) predispose individuals to the development of skin tumors that include cylindromas, spiradenomas and trichoepitheliomas
The extensive homology between the deubiquitinating domain of HsCyld encodes a deubiquitinating enzyme (HsCYLD) and the corresponding region of CeCYLD prompted an investigation into the ability of CeCYLD to act a deubiquitinating enzyme [18]
The deubiquitinating activity of HsCYLD depends on several amino acid residues of the active site including cysteine 601 (C601)
Summary
Inactivating mutations in the human Cyld gene (HsCyld) predispose individuals to the development of skin tumors that include cylindromas, spiradenomas and trichoepitheliomas (reviewed in [1]). A tumor suppressing activity of HsCyld has been associated with several other types of human malignancies including multiple myeloma, melanoma, breast colon and hepatocellular carcinoma [2,3,4,5,6]. These findings have fueled an intense effort to understand the molecular mechanisms that underlie the homeostatic functions of HsCyld.
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