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

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.

• Authors: Jun Zhang, Brigid Stirling, Stephane T Temmerman, Chi A Ma, Ivan J Fuss, Jonathan M J Derry, Ashish Jain
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 116 Issue 11 Pg. 3042-9 (Nov 2006) ISSN: 0021-9738 [Print] United States
• PMID: 17053834 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• 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)