Impaired regulation of NF-κB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice
Jun Zhang, … , Jonathan M.J. Derry, Ashish Jain
Jun Zhang, … , Jonathan M.J. Derry, Ashish Jain
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):3042-3049. https://doi.org/10.1172/JCI28746.
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Research Article Oncology

Impaired regulation of NF-κB 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-κB and JNK activity associated with increased TNF receptor–associated factor 2 (TRAF2) and NF-κB 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

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Figure 7

COX-2 and iNOS immunostaining of tissue sections obtained from wild-type and Cyld–/–mice 7 days after the first, second, and third cycles of DSS treatment.

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COX-2 and iNOS immunostaining of tissue sections obtained from wild-type...
Numerous COX-2–positive cells were observed in the epithelium, and iNOS-positive cells were observed within broadly based inflammatory infiltrating cells, of the adenomatous tissue of Cyld–/– mice. Arrowheads indicate positively stained cells. Magnification, ×50.