Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice.
Cylindromatosis (CYLD) is a deubiquitinating enzyme that is altered in patients with familial cylindromatosis, a condition characterized by numerous benign adnexal tumors. However, the regulatory function of CYLD remains unsettled. Here we show that the development of B cells, T cells, and myeloid cells was unaffected in CYLD-deficient mice, but that the activation of these cells with mediators of innate and adaptive immunity resulted in enhanced NF-kappaB and JNK activity associated with increased TNF receptor-associated factor 2 (TRAF2) and NF-kappaB essential modulator (NEMO) ubiquitination. CYLD-deficient mice were more susceptible to induced colonic inflammation and showed a dramatic increase in the incidence of tumors compared with controls in a colitis-associated cancer model. These results suggest that CYLD limits inflammation and tumorigenesis by regulating ubiquitination in vivo.
Zhang
Jun
J
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA.
Stirling
Brigid
B
Temmerman
Stephane T
ST
Ma
Chi A
CA
Fuss
Ivan J
IJ
Derry
Jonathan M J
JM
Jain
Ashish
A
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003092:Colitis / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D025801:Ubiquitin; D048031:JNK Mitogen-Activated Protein Kinases; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases