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PMID: 17053834 Published · ppublish English Journal Article

Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice.

The Journal of clinical investigation ·Vol. 116 ·No. 11 ·2006-11-00 ·Pages 3042-9

Zhang J, Stirling B, Temmerman ST, Ma CA, Fuss IJ, Derry JM, Jain A

Abstract

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.

MeSH Terms
Animals Cell Transformation, Neoplastic/genetics,metabolism,pathology Colitis/complications,genetics,metabolism,pathology Colonic Neoplasms/etiology,genetics,metabolism,pathology Cysteine Endopeptidases/deficiency,genetics,metabolism Cytokines/biosynthesis Deubiquitinating Enzyme CYLD Enzyme Activation Genetic Predisposition to Disease/genetics Intracellular Signaling Peptides and Proteins/metabolism JNK Mitogen-Activated Protein Kinases/metabolism Macrophages/metabolism Mice Mice, Knockout NF-kappa B/metabolism Phenotype Protein Binding TNF Receptor-Associated Factor 2/metabolism Ubiquitin/metabolism
Chemicals
Cytokines Intracellular Signaling Peptides and Proteins NEMO protein, mouse NF-kappa B TNF Receptor-Associated Factor 2 Ubiquitin JNK Mitogen-Activated Protein Kinases CYLD protein, mouse Deubiquitinating Enzyme CYLD Cysteine Endopeptidases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Zhang Jun
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA.
Stirling Brigid
Temmerman Stephane T
Ma Chi A
Fuss Ivan J
Derry Jonathan M J
Jain Ashish
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI28746
Published
2006-11-00
Epub
2006-00-19
Pages
3042-9
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1616194
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI28746 PMC Full Text View journal details
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