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Molecular and Cellular Biology, April 1999, p. 2475-2484, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Double-Stranded-RNA-Activated Protein Kinase PKR Enhances Transcriptional Activation by Tumor Suppressor p53

Andrew R. Cuddihy,1 Suiyang Li,1 Nancy Wai Ning Tam,1 Andrew Hoi-Tao Wong,1 Yoichi Taya,2 Ninan Abraham,3 John C. Bell,3 and Antonis E. Koromilas1,4,5,*

Departments of Oncology and Medicine,1 Microbiology and Immunology,4 and Anatomy and Cell Biology,5 McGill University, Montreal, Quebec, and Department of Medicine and Biochemistry, University of Ottawa, Ottawa, Ontario,3 Canada, and Biology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan2

Received 28 September 1998/Returned for modification 22 October 1998/Accepted 21 December 1998

The tumor suppressor p53 plays a key role in inducing G1 arrest and apoptosis following DNA damage. The double-stranded-RNA-activated protein PKR is a serine/threonine interferon (IFN)-inducible kinase which plays an important role in regulation of gene expression at both transcriptional and translational levels. Since a cross talk between IFN-inducible proteins and p53 had already been established, we investigated whether and how p53 function was modulated by PKR. We analyzed p53 function in several cell lines derived from PKR+/+ and PKR-/- mouse embryonic fibroblasts (MEFs) after transfection with the temperature-sensitive (ts) mutant of mouse p53 [p53(Val135)]. Here we report that transactivation of transcription by p53 and G0/G1 arrest were impaired in PKR-/- cells upon conditions that ts p53 acquired a wild-type conformation. Phosphorylation of mouse p53 on Ser18 was defective in PKR-/- cells, consistent with an impaired transcriptional induction of the p53-inducible genes encoding p21WAF/Cip1 and Mdm2. In addition, Ser18 phosphorylation and transcriptional activation by mouse p53 were diminished in PKR-/- cells after DNA damage induced by the anticancer drug adriamycin or gamma  radiation but not by UV radiation. Furthermore, the specific phosphatidylinositol-3 (PI-3) kinase inhibitor LY294002 inhibited the induction of phosphorylation of Ser18 of p53 by adriamycin to a higher degree in PKR+/+ cells than in PKR-/- cells. These novel findings suggest that PKR enhances p53 transcriptional function and implicate PKR in cell signaling elicited by a specific type of DNA damage that leads to p53 phosphorylation, possibly through a PI-3 kinase pathway.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal, Quebec H3T 1E2, Canada. Phone: (514) 340-8260, ext. 4504. Fax: (514) 340-7576. E-mail: akoromil{at}ldi.jgh.mcgill.ca.

Molecular and Cellular Biology, April 1999, p. 2475-2484, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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