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Originally published In Press as doi:10.1074/jbc.M008140200 on February 5, 2001

J. Biol. Chem., Vol. 276, Issue 17, 13881-13890, April 27, 2001
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Dominant Negative Function by an Alternatively Spliced Form of the Interferon-inducible Protein Kinase PKR*

Suiyang LiDagger and Antonis E. KoromilasDagger §

From the Dagger  Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Québec H3T 1E2, Canada and the § Departments of Oncology, Medicine, Microbiology and Immunology, and Cell Biology and Anatomy, McGill University, Montréal, Québec H3A 2B4, Canada

The double-stranded RNA (dsRNA)-activated protein kinase PKR (protein kinase dsRNA-dependent) plays an important role in the regulation of protein synthesis by phosphorylating the alpha -subunit of eukaryotic initiation factor 2. Through this activity, PKR is thought to mediate the antiviral and antiproliferative actions of interferon. Here, we show that the human T cell leukemia Jurkat cells express an alternatively spliced form of PKR with a deletion of exon 7 (PKRDelta E7), resulting in a truncated protein that retains the two dsRNA-binding motifs. PKRDelta E7 exhibits a dominant negative function by inhibiting both PKR autophosphorylation and eukaryotic initiation factor 2 alpha -subunit phosphorylation in vitro and in vivo. Reverse transcriptase-polymerase chain reaction assays showed that PKRDelta E7 is expressed in a broad range of human tissues at variable levels. Interestingly, expression of PKRDelta E7 is higher in Jurkat cells than in normal peripheral blood mononuclear cells, raising the possibility of a role in cell proliferation and/or transformation. Thus, expression of alternatively spliced forms of PKR may represent a novel mechanism of PKR autoregulation with important implications in the control of cell proliferation.

* This work was supported by a grant and a postdoctoral fellowship from the Cancer Research Society Inc. (to A. E. K. and S. L., respectively).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.

Member of the Terry Fox Group of Molecular Oncology and a recipient of a Canadian Institutes of Health Research Scientist Award. To whom correspondence should be addressed: Lady Davis Institute for Medical Research, Rm. 508, Jewish General Hospital, 3755 Côte-Ste-Catherine St., Montréal, Québec, Canada H3T 1E2. 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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