title: Direct inhibition of TNF-α promoter activity by Fanconi anemia protein FANCD2.
abstract: Fanconi anemia (FA), an inherited disease, is associated with progressive bone marrow failure, predisposition to cancer, and genomic instability. Genes corresponding to 15 identified FA complementation groups have been cloned, and each gene product functions in the response to DNA damage induced by cross-linking agents and/or in protection against genome instability. Interestingly, overproduction of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and aberrant activation of NF-κB-dependent transcriptional activity have been observed in FA cells. Here we demonstrated that FANCD2 protein inhibits NF-κB activity in its monoubiquitination-dependent manner. Furthermore, we detected a specific association between FANCD2 and an NF-κB consensus element in the TNF-α promoter by electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assay. Therefore, we propose FANCD2 deficiency promotes transcriptional activity of the TNF-α promoter and induces overproduction of TNF-which then sustains prolonged inflammatory responses. These results also suggest that artificial modulation of TNFα production could be a promising therapeutic approach to FA.
authors.affiliation: Laboratory of Molecular Biochemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan. matsun@ls.toyaku.ac.jp
authors.forename: Nobuko
authors.initials: N
authors.lastname: Matsushita
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Endo
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurumizaka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamashita
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yanagi
mesh_terms: D016384:Consensus Sequence; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha