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Originally published In Press as doi:10.1074/jbc.M209386200 on October 22, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49638-49643, December 20, 2002
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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 PangDagger §, Tracy A. ChristiansonDagger , Winifred KeebleDagger , Tara KoretskyDagger , and Grover C. BagbyDagger §

From the Dagger  OHSU Cancer Institute, Department of Medicine and Molecular and Medical Genetics, Oregon Health and Science University and § Veterans Affairs Medical Center, Portland, Oregon 97201

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.

* This work was supported in part by National Institutes of Health Grant HL48546 (to G. C. B.) and a grant from the Northwest Health Foundation (to Q. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: OHSU Cancer Institute, CR145, Oregon Health Sciences University, Portland, OR 97201. E-mail: grover@ohsu.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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