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TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers
Title: | TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers |
Authors: | Noguchi, Keita Browse this author | Okumura, Fumihiko Browse this author | Takahashi, Norihiko Browse this author | Kataoka, Akihiko Browse this author | Kamiyama, Toshiya Browse this author | Todo, Satoru Browse this author →KAKEN DB | Hatakeyama, Shigetsugu Browse this author →KAKEN DB |
Keywords: | TRIM40 | Nedd8 | IKKγ | NF-κB | gastrointestinal cancer |
Issue Date: | Jul-2011 |
Publisher: | Oxford University Press |
Journal Title: | Carcinogenesis |
Volume: | 32 |
Issue: | 7 |
Start Page: | 995 |
End Page: | 1004 |
Publisher DOI: | 10.1093/carcin/bgr068 |
PMID: | 21474709 |
Abstract: | 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. |
Rights: | 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 |
Type: | article (author version) |
URI: | http://hdl.handle.net/2115/49481 |
Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 畠山 鎮次
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