TRIM40 promotes neddylation of IKKgamma and is downregulated in gastrointestinal cancers.
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Noguchi K, Okumura F, Takahashi N, Kataoka A, Kamiyama T, Todo S, Hatakeyama S
TRIM40 promotes neddylation of IKKgamma and is downregulated in gastrointestinal cancers.
Carcinogenesis. 2011 Jul;32(7):995-1004. doi: 10.1093/carcin/bgr068. Epub 2011 Apr 7.
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- 21474709 [ View in PubMed]
- Abstract
Gastrointestinal neoplasia seems to be a common consequence of chronic inflammation in the gastrointestinal epithelium. Nuclear factor-kappaB (NF-kappaB) 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-kappaB is regulated by several posttranslational modifications including phosphorylation, ubiquitination and neddylation. In this study, we showed that tripartite motif (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 inhibitor of nuclear factor kappaB kinase subunit gamma, which is a crucial regulator for NF-kappaB activation, and consequently causes inhibition of NF-kappaB activity, whereas a dominant-negative mutant of TRIM40 lacking the RING domain does not inhibit NF-kappaB activity. Knockdown of TRIM40 in the small intestinal epithelial cell line IEC-6 caused NF-kappaB 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-kappaB activity via neddylation of inhibitor of nuclear factor kappaB kinase subunit gamma and that TRIM40 prevents inflammation-associated carcinogenesis in the gastrointestinal tract.