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Blood, 1 August 2006, Vol. 108, No. 3, pp. 821-829. Prepublished online as a Blood First Edition Paper on April 11, 2006; DOI 10.1182/blood-2005-11-006817. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2005-11-006817v1 108/3/821    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bennett, R. L. Articles by May, W. S. Search for Related Content PubMed PubMed Citation Articles by Bennett, R. L. Articles by May, W. S. Related Collections Apoptosis Signal Transduction Chemokines, Cytokines, and Interleukins Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS RAX, the PKR activator, sensitizes cells to inflammatory cytokines, serum withdrawal, chemotherapy, and viral infection Richard L. Bennett, William L. Blalock, Dean M. Abtahi, Yu Pan, Sue A. Moyer, and W. Stratford May From the Shands Cancer Center and Department of Immunology and Molecular Genetics, University of Florida, Gainesville, Florida; and Department of Innovative Therapy, Advanced Biotechnology Center, Genoa, Italy. While the interferon (IFN)–inducible double-stranded RNA (dsRNA)–dependent protein kinase PKR is reported to initiate apoptosis in some instances, the mechanism by which diverse stress stimuli activate PKR remains unknown. Now we report that RAX, the only known cellular activator for PKR, initiates PKR activation in response to a broad range of stresses including serum deprivation, cytotoxic cytokine or chemotherapy treatment, or viral infection. Thus, knock-down of RAX expression by 80% using small interfering RNA (siRNA) prevents IFN/tumor necrosis factor (TNF)–induced PKR activation and eIF2 phosphorylation, IB degradation, IRF-1 expression, and STAT1 phosphorylation, resulting in enhanced murine embryonic fibroblast (MEF) cell survival. In contrast, expression of exogenous RAX, but not of the nonphosphorylatable, dominant-negative RAX(S18A) mutant, sensitizes cells to IFN/TNF, mitomycin C (MMC), or serum deprivation in association with increased PKR activity and apoptosis. Furthermore, RAX(S18A) expression in Fanconi anemia complementation group C–null MEF cells not only prevents PKR activation but also blocks hypersensitivity to IFN/TNF or mitomycin C that results in enhanced apoptosis. In addition, reduced RAX expression facilitates productive viral infection with vesicular stomatitis virus (VSV) and promotes anchorage-independent colony growth of MEF cells. Collectively, these data indicate that RAX may function as a negative regulator of growth that is required to activate PKR in response to a broad range of apoptosis-inducing stress. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. H. Kok, M.-H. J. Ng, Y.-P. Ching, and D.-Y. Jin Human TRBP and PACT Directly Interact with Each Other and Associate with Dicer to Facilitate the Production of Small Interfering RNA J. Biol. Chem., June 15, 2007; 282(24): 17649 - 17657. [Abstract] [Full Text] [PDF] M. Yang, S. Wu, X. Su, and W. S. May JAZ mediates G1 cell-cycle arrest and apoptosis by positively regulating p53 transcriptional activity Blood, December 15, 2006; 108(13): 4136 - 4145. [Abstract] [Full Text] [PDF]

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