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* Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60611;
Division of Cell and Molecular Biology, Toronto Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Canada;
Division of Hematology-Oncology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; and
Division of Signal Transduction, Beth Israel Medical Center, Harvard Medical School, Boston, MA 02115
PI3K is activated by the type I and II IFN receptors, but its precise role in the generation of IFN responses is not well understood. In the present study we used embryonic fibroblasts from mice with targeted disruption of the genes encoding for both the p85
and p85β regulatory subunits of PI3'-kinase (p85–/–β–/–) to precisely define the role of PI3K in the control of IFN-induced biological responses. Our data demonstrate that PI3K plays dual regulatory roles in the induction of IFN responses by controlling both IFN-- and IFN-
-dependent transcriptional regulation of IFN-sensitive genes and simultaneously regulating the subsequent initiation of mRNA translation for such genes. These processes include the Isg15, Cxcl10, and/or Irf7 genes, whose functions are important in the generation of the biological effects of IFNs. Consistent with this, the induction of IFN antiviral responses is defective in double p85/p85β knockout cells. Thus, integration of signals via PI3K is a critical event during engagement of the IFN receptors that complements both the transcriptional activity of Jak-STAT pathways and controls initiation of mRNA translation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants CA77816, CA100579, CA121192, AG029138, and HL082946, a Merit Review Grant from the Department of Veterans Affairs, and Canadian Institutes of Health Research Grant MOP 15094.
2 Current address: Novartis Pharma, WKL-125.4.01A, Klybeckstrasse 141, CH-4057 Basel, Switzerland.
3 Address correspondence and reprint requests to Dr. Leonidas C. Platanias, Robert H. Lurie Comprehensive Cancer Center, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611. E-mail address: l-platanias{at}northwestern.edu
4 Abbreviations used in this paper: ISG, IFN-stimulated gene; ECMV, encephalomyocarditis virus; 4E-BP, eukaryotic initiation factor 4E-binding protein; GAS, IFN- activated site; IRS, insulin receptor substrate; ISRE, IFN stimulated response element; MEF, mouse embryonic fibroblast; mTOR, mammalian target of rapamycin.
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