Functional correction of FA-C cells with FANCC suppresses the expression of interferon γ-inducible genes

Sara R. Fagerlie, Jane Diaz, Tracy A. Christianson, Kelli McCartan, Winifred Keeble, Gregory R. Faulkner, Grover C. Bagby

    Research output: Contribution to journalArticle

    40 Scopus citations


    Because hematopoietic cells derived from Fanconi anemia (FA) patients of the C-complementation group (FA-C) are hypersensitive to the inhibitory effects of interferon γ (IFN-γ), the products of certain IFNγ-inducible genes known to influence hematopoietic cell survival were quantified. High constitutive expression of the IFNγ-inducible genes, IFN-stimulated gene factor 3 gamma subunit (ISGF3γ), IFN regulatory factor-1 (IRF-1), and the cyclin-dependent kinase inhibitor p21WAF1 was found in FANCC mutant B lymphoblasts, low-density bone marrow cells, and murine embryonic fibroblasts. Paradoxically, these cells do not activate signal transducer and activator of transcription (STAT) 1 properly. In an attempt to clarify mechanisms by which FA-C cells overexpress IFNγ-inducible genes in the face of defective STAT1 phosphorylation, it was reasoned that decreased levels of activated STAT1 might result in reduced expression of a hematopoietic IFNγ-responsive protein that normally modulates expression of other IFNγ-responsive genes. Levels of the IFNγ-inducible factor IFN consensus sequence binding protein (ICSBP), a negative trans-acting regulator of some IFNγ-inducible genes, were quantified. ICSBP levels were reduced in FA-C B lymphoblasts and MEFs. However, enforced expression of ICSBP failed to down-regulate IRF-1, ISGF3γ, and p21WAF1. Thus, the FANCC protein functions to modulate expression of a family of genes that in normal cells are inducible only by specific environmental cues for apoptosis or mitogenic inhibition, but it does so independently of the classic IFN-STAT1 pathway and is not the direct result of reduced ICSBP expression.

    Original languageEnglish (US)
    Pages (from-to)3017-3024
    Number of pages8
    Issue number10
    StatePublished - May 15 2001


    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Cite this

    Fagerlie, S. R., Diaz, J., Christianson, T. A., McCartan, K., Keeble, W., Faulkner, G. R., & Bagby, G. C. (2001). Functional correction of FA-C cells with FANCC suppresses the expression of interferon γ-inducible genes. Blood, 97(10), 3017-3024.