open access

https://hdl.handle.net/2115/49481

TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers

英語

gastrointestinal cancer

2011-07

Oxford University Press

Carcinogenesis

32(7)

995-1004

Gastrointestinal neoplasia seems to be a common consequence of chronic inflammation in the gastrointestinal epithelium. NF-κB is an important transcription factor for carcinogenesis in chronic inflammatory diseases and plays a key role in promoting inflammation-associated carcinoma in the gastrointestinal tract. Activation of NF-κB is regulated by several posttranslational modifications including phosphorylation, ubiquitination and neddylation. In this study, we showed that TRIM 40 is highly expressed in the gastrointestinal tract and that TRIM40 physically binds to Nedd8, which is conjugated to target proteins by neddylation. We also found that TRIM40 promotes the neddylation of IKKγ, which is a crucial regulator for NF-κB activation, and consequently causes inhibition of NF-κB activity, whereas a dominant-negative mutant of TRIM40 lacking the RING domain does not inhibit NF-κB activity. Knockdown of TRIM40 in the small intestinal epithelial cell line IEC-6 caused NF-κB activation followed by increased cell growth. In addition, we found that TRIM40 is highly expressed in normal gastrointestinal epithelia but that TRIM40 is downregulated in gastrointestinal carcinomas and chronic inflammatory lesions of the gastrointestinal tract. These findings suggest that TRIM40 inhibits NF-κB activity via neddylation of IKKγ and that TRIM40 prevents inflammation-associated carcinogenesis in the gastrointestinal tract.

学術雑誌論文

Accepted Manuscript

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The definitive publisher-authenticated version Carcinogenesis (2011) 32(7): 995-1004 is available online at: http://carcin.oxfordjournals.org/content/32/7/995

0143-3334