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.

[1]  G. Wagner.  Epithelioma Adenoides Cysticum Brooke , 2007 .

[2]  Ramin Massoumi,et al.  Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF-κB Signaling , 2006, Cell.

[3]  C. Fathman,et al.  CYLD: deubiquitination-induced TCR signaling , 2006, Nature Immunology.

[4]  Shao-Cong Sun,et al.  Regulation of T cell development by the deubiquitinating enzyme CYLD , 2006, Nature Immunology.

[5]  Chuanshu Huang,et al.  Inflammation, a Key Event in Cancer Development , 2006, Molecular Cancer Research.

[6]  Zhijian J. Chen.  Ubiquitin signalling in the NF-κB pathway , 2005, Nature Cell Biology.

[7]  C. Cockerell,et al.  Cutaneous appendage tumors: familial cylindromatosis and associated tumors update. , 2005, Advances in dermatology.

[8]  Shao-Cong Sun,et al.  Negative Regulation of JNK Signaling by the Tumor Suppressor CYLD* , 2004, Journal of Biological Chemistry.

[9]  Matthew T Wheeler,et al.  The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses , 2004, Nature Immunology.

[10]  Hans Clevers,et al.  At the Crossroads of Inflammation and Cancer , 2004, Cell.

[11]  Michael Karin,et al.  IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer , 2004, Cell.

[12]  Somasekar Seshagiri,et al.  De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling , 2004, Nature.

[13]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[14]  Z. Ronai,et al.  Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF‐κB , 2004, The EMBO journal.

[15]  Honglin Zhou,et al.  Bcl10 activates the NF-κB pathway through ubiquitination of NEMO , 2004, Nature.

[16]  Honglin Zhou,et al.  Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. , 2004, Nature.

[17]  René Bernards,et al.  Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB , 2003, Nature.

[18]  A. Ashworth,et al.  CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members , 2003, Nature.

[19]  G. Courtois,et al.  The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination , 2003, Nature.

[20]  J. Tschopp,et al.  Recruitment of TNF Receptor 1 to Lipid Rafts Is Essential for TNFα-Mediated NF-κB Activation , 2003 .

[21]  K. Washington,et al.  Pathology of mouse models of intestinal cancer: consensus report and recommendations. , 2003, Gastroenterology.

[22]  J. Tschopp,et al.  Recruitment of TNF receptor 1 to lipid rafts is essential for TNFalpha-mediated NF-kappaB activation. , 2003, Immunity.

[23]  D. Goeddel,et al.  TNF-R1 Signaling: A Beautiful Pathway , 2002, Science.

[24]  Inder M Verma,et al.  NF-kappaB regulation in the immune system. , 2002, Nature reviews. Immunology.

[25]  Y. Ben-Neriah.  Regulatory functions of ubiquitination in the immune system , 2002, Nature Immunology.

[26]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[27]  A. Ashworth,et al.  Identification of the familial cylindromatosis tumour-suppressor gene , 2000, Nature Genetics.

[28]  E. Koonin,et al.  A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae. , 2000, Trends in biochemical sciences.

[29]  Stefan Grimm,et al.  The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal , 1998 .

[30]  P. Leder,et al.  The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. , 1998, Immunity.

[31]  Peskin Av.  Interaction of reactive oxygen species with DNA. A review. , 1997 .

[32]  A. Peskin.  Interaction of reactive oxygen species with DNA. A review. , 1997, Biochemistry. Biokhimiia.

[33]  B. Seed,et al.  RIP mediates tumor necrosis factor receptor 1 activation of NF‐kappaB but not Fas/APO‐1‐initiated apoptosis. , 1996, The EMBO journal.

[34]  T. Ohkusa,et al.  Promotion of colorectal neoplasia in experimental murine ulcerative colitis. , 1996, Gut.

[35]  M. Stratton,et al.  Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12–q13: evidence for its role as a tumour suppressor gene , 1995, Nature Genetics.

[36]  R. Pascal.  Dysplasia and early carcinoma in inflammatory bowel disease and colorectal adenomas. , 1994, Human pathology.

[37]  A E Pegg,et al.  Methylation of the O6 position of guanine in DNA is the most likely initiating event in carcinogenesis by methylating agents. , 1984, Cancer investigation.

[38]  D. Ransohoff,et al.  Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. , 1983, Human pathology.

[39]  L. Savatard.  EPITHELIOMA ADENOIDES CYSTICUM , 1922 .