Direct inhibition of tnf-α promoter activity by fanconi anemia protein fancd2

Nobuko Matsushita, Yujiro Endo, Koichi Sato, Hitoshi Kurumizaka, Takayuki Yamashita, Minoru Takata, Shigeru Yanagi

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    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.

    Original languageEnglish
    Article numbere23324
    JournalPLoS One
    Volume6
    Issue number8
    DOIs
    Publication statusPublished - 2011

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

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    Matsushita, N., Endo, Y., Sato, K., Kurumizaka, H., Yamashita, T., Takata, M., & Yanagi, S. (2011). Direct inhibition of tnf-α promoter activity by fanconi anemia protein fancd2. PLoS One, 6(8), [e23324]. https://doi.org/10.1371/journal.pone.0023324