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C., Jr Related Collections Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 March 2001, Vol. 97, No. 6, pp. 1644-1652 HEMATOPOIESIS Role of double-stranded RNA-dependent protein kinase in mediating hypersensitivity of Fanconi anemia complementation group C cells to interferon , tumor necrosis factor-, and double-stranded RNA Qishen Pang, Winifred Keeble, Jane Diaz, Tracy A. Christianson, Sara Fagerlie, Keaney Rathbun, Gregory R. Faulkner, Michael O'Dwyer, and Grover C. Bagby Jr From the Oregon Cancer Center, Division of Hematology and Medical Oncology, Department of Medicine, and Department of Molecular and Medical Genetics, Oregon Health Sciences University; and Molecular Hematopoiesis Laboratory, VA Medical Center, Portland, Oregon. Hematopoietic cells bearing inactivating mutations of Fanconi anemia group C (FANCC) are excessively apoptotic and demonstrate hypersensitivity not only to cross-linking agents but also to interferon  (IFN-) and tumor necrosis factor-. Seeking essential signaling pathways for this phenotype, this study quantified constitutive and induced RNA-dependent protein kinase (PKR) activation in Fanconi anemia cells of the C complementation group (FA-C). PKR was constitutively phosphorylated and exhibited an increased binding affinity for double-stranded RNA (dsRNA) in FANCC/ cells. FANCC/ cells were hypersensitive to both dsRNA and the combination of dsRNA and IFN- in that these agents induced a higher fraction of apoptosis in FANCC/ cells than in normal cells. Overexpression of wild-type PKR-sensitized FANCC/ cells to apoptosis induced by IFN- and dsRNA. Conversely, inhibition of PKR function by enforced expression of a dominant-negative inhibitory mutant of PKR (PKR6) substantially reduced the IFN and dsRNA hypersensitivity of FANCC/ cells. Two PKR target molecules, IB- and IRF-1, were not differentially activated in FANCC/ cells, but enforced expression of a nonphosphorylatable form of eukaryotic translation initiation factor-2 reversed the PKR-mediated block of messenger RNA translation and partially abrogated the PKR-mediated apoptosis in FANCC/ cells. Because no evidence was found of a PKR/FANCC complex in normal cells, it was concluded that an essential function of FANCC is to suppress, indirectly, the activity of PKR and that FANCC inactivation results in IFN hypersensitivity, at least in part, because this function of FANCC is abrogated. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. L. 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	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020