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Originally published In Press as doi:10.1074/jbc.M011240200 on January 25, 2001

J. Biol. Chem., Vol. 276, Issue 17, 13727-13737, April 27, 2001
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Enhanced Antiviral and Antiproliferative Properties of a STAT1 Mutant Unable to Interact with the Protein Kinase PKR*

Andrew Hoi-Tao WongDagger §, Joan E. Durbin, Suiyang LiDagger ||, Thomas E. Dever**, Thomas DeckerDagger Dagger , and Antonis E. KoromilasDagger §§

From the Dagger  Terry Fox Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal H3T 1E2, Canada, the  Children's Hospital Research Foundation and Department of Pediatrics, Ohio State University, Columbus, Ohio 43205, the ** Laboratory of Eukaryotic Gene Expression, NICHD, National Institutes of Health, Bethesda, Maryland 20892, and the Dagger Dagger  Vienna Biocenter, Institute for Microbiology and Genetics, Vienna 1030, Austria

We have previously reported a physical association between STAT1 and the protein kinase double-stranded RNA-activated protein kinase (PKR). PKR inhibited STAT1 function in a manner independent of PKR kinase activity. In this report, we have further characterized the properties of both molecules by mapping the sites of their interaction. A STAT1 mutant unable to interact with PKR displays enhanced interferon gamma  (IFN-gamma )-induced transactivation capacity compared with STAT1. This effect appears to be mediated by the higher capacity of STAT1 mutant to heterodimerize with STAT3. Furthermore, expression of STAT1 mutant in STAT1-/- cells enhances both the antiviral and antiproliferative effects of IFNs as opposed to STAT1. We also provide evidence that STAT1 functions as an inhibitor of PKR in vitro and in vivo. That is, phosphorylation of eIF-2alpha is enhanced in STAT1-/- than STAT1+/+ cells in vivo, and this correlates with higher activation capacity of PKR in STAT1-/- cells. Genetic experiments in yeast demonstrate the inhibition of PKR activation and eIF-2alpha phosphorylation by STAT1 but not by STAT1 mutant. These data substantiate our previous findings on the inhibitory effects of PKR on STAT1 and implicate STAT1 in translational control through the modulation of PKR activation and eIF-2alpha phosphorylation.

* This work was supported in part by research grants from the Canadian Institutes of Health Research and the Human Frontier Science Program (to A. E. K.).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.

§ Recipient of a National Cancer Institute of Canada, Terry Fox studentship. Present address: The Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016.

|| Recipient of a post-doctoral award from the Cancer Research Society of Canada.

§§ A member of the Terry Fox Group in Molecular Oncology and recipient of a Canadian Institutes of Health Research Scientist Award. To whom correspondence should be addressed: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal, Quebec H3T 1E2, Canada. Tel.: 514-340-8260 (ext. 3697); Fax: 514-340-7576; E-mail: akoromil@ ldi.jgh.mcgill.ca.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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