The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC

Qishen Pang, Tracy A. Christianson, Winifred Keeble, Tara Koretsky, Grover C. Bagby

    Research output: Contribution to journalArticle

    77 Citations (Scopus)

    Abstract

    Proteins encoded by five of the six known Fanconi anemia (FA) genes form a heteromeric complex that facilitates repair of DNA damage induced by cross-linking agents. A certain number of these proteins, notably FANCC, also function independently to modulate apoptotic signaling, at least in part, by suppressing ground state activation of the pro-apoptotic interferon-inducible double-stranded RNA-dependent protein kinase (PKR). Because certain FANCC mutations interdict its anti-apoptotic function without interfering with the capacity of FANCC to participate functionally in the FA multimeric complex, we suspected that FANCC enhances cell survival independent of its participation in the complex. By investigating this function in both mammalian cells and in yeast, an organism with no FA orthologs, we show that FANCC inhibited the kinase activity of PKR both in vivo and in vitro, and this effect depended upon a physical interaction between FANCC and Hsp70 but not on interactions of FANCC with other Fanconi proteins. Hsp70, FANCC, and PKR form a ternary complex in lymphoblasts and in yeast expressing PKR. We conclude that Hsp70 requires the cooperation of FANCC to suppress PKR activity and support survival of hematopoietic cells and that FANCC does not require the multimeric FA complex to exert this function.

    Original languageEnglish (US)
    Pages (from-to)49638-49643
    Number of pages6
    JournalJournal of Biological Chemistry
    Volume277
    Issue number51
    DOIs
    StatePublished - Dec 20 2002

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    Fanconi Anemia Complementation Group Proteins
    eIF-2 Kinase
    Fanconi Anemia
    Double-Stranded RNA
    Interferons
    Cells
    Fanconi Anemia Complementation Group C Protein
    Yeast
    Cell Survival
    Yeasts
    Ground state
    Proteins
    Repair
    Phosphotransferases
    Genes
    Chemical activation
    DNA Damage
    DNA
    Mutation

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC. / Pang, Qishen; Christianson, Tracy A.; Keeble, Winifred; Koretsky, Tara; Bagby, Grover C.

    In: Journal of Biological Chemistry, Vol. 277, No. 51, 20.12.2002, p. 49638-49643.

    Research output: Contribution to journalArticle

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