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

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    Abstract

    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
    JournalBlood
    Volume97
    Issue number10
    DOIs
    StatePublished - May 15 2001

    Fingerprint

    Fanconi Anemia
    Interferons
    Genes
    Gamma Subunit Interferon-Stimulated Gene Factor 3
    Fanconi Anemia Complementation Group C Protein
    Cells
    CDC2 Protein Kinase
    STAT1 Transcription Factor
    Phosphorylation
    Fibroblasts
    Bone Marrow Cells
    Cues
    Cell Survival
    Bone
    Down-Regulation
    Apoptosis

    ASJC Scopus subject areas

    • Hematology

    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. https://doi.org/10.1182/blood.V97.10.3017

    Functional correction of FA-C cells with FANCC suppresses the expression of interferon γ-inducible genes. / Fagerlie, Sara R.; Diaz, Jane; Christianson, Tracy A.; McCartan, Kelli; Keeble, Winifred; Faulkner, Gregory R.; Bagby, Grover C.

    In: Blood, Vol. 97, No. 10, 15.05.2001, p. 3017-3024.

    Research output: Contribution to journalArticle

    Fagerlie, SR, Diaz, J, Christianson, TA, McCartan, K, Keeble, W, Faulkner, GR & Bagby, GC 2001, 'Functional correction of FA-C cells with FANCC suppresses the expression of interferon γ-inducible genes', Blood, vol. 97, no. 10, pp. 3017-3024. https://doi.org/10.1182/blood.V97.10.3017
    Fagerlie SR, Diaz J, Christianson TA, McCartan K, Keeble W, Faulkner GR et al. Functional correction of FA-C cells with FANCC suppresses the expression of interferon γ-inducible genes. Blood. 2001 May 15;97(10):3017-3024. https://doi.org/10.1182/blood.V97.10.3017
    Fagerlie, Sara R. ; Diaz, Jane ; Christianson, Tracy A. ; McCartan, Kelli ; Keeble, Winifred ; Faulkner, Gregory R. ; Bagby, Grover C. / Functional correction of FA-C cells with FANCC suppresses the expression of interferon γ-inducible genes. In: Blood. 2001 ; Vol. 97, No. 10. pp. 3017-3024.
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