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Molecular and Cellular Biology, July 1999, p. 4757-4765, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibition of Double-Stranded RNA- and Tumor Necrosis Factor Alpha-Mediated Apoptosis by Tetratricopeptide Repeat Protein and Cochaperone P58IPK

Norina M. Tang,1 Marcus J. Korth,2 Michael Gale Jr.,1 Marlene Wambach,2 Sandy D. Der,3 Sudip K. Bandyopadhyay,3 Bryan R. G. Williams,3 and Michael G. Katze1,2,*

Department of Microbiology1 and Washington Regional Primate Research Center,2 University of Washington, Seattle, Washington 98195, and Department of Cancer Biology, Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 441953

Received 17 December 1998/Returned for modification 8 February 1999/Accepted 28 April 1999

P58IPK is a tetratricopeptide repeat-containing cochaperone that is involved in stress-activated cellular pathways and that inhibits the activity of protein kinase PKR, a primary mediator of the antiviral and antiproliferative properties of interferon. To gain better insight into the molecular actions of P58IPK, we generated NIH 3T3 cell lines expressing either wild-type P58IPK or a P58IPK deletion mutant, Delta TPR6, that does not bind to or inhibit PKR. When treated with double-stranded RNA (dsRNA), Delta TPR6-expressing cells exhibited a significant increase in eukaryotic initiation factor 2alpha phosphorylation and NF-kappa B activation, indicating a functional PKR. In contrast, both of these PKR-dependent events were blocked by the overexpression of wild-type P58IPK. In addition, the P58IPK cell line, but not the Delta TPR6 cell line, was resistant to dsRNA-induced apoptosis. Together, these findings demonstrate that P58IPK regulates dsRNA signaling pathways by inhibiting multiple PKR-dependent functions. In contrast, both the P58IPK and Delta TPR6 cell lines were resistant to tumor necrosis factor alpha-induced apoptosis, suggesting that P58IPK may function as a more general suppressor of programmed cell death independently of its PKR-inhibitory properties. In accordance with this hypothesis, although PKR remained active in Delta TPR6-expressing cells, the Delta TPR6 cell line displayed a transformed phenotype and was tumorigenic in nude mice. Thus, the antiapoptotic function of P58IPK may be an important factor in its ability to malignantly transform cells.

* Corresponding author. Mailing address: Department of Microbiology, University of Washington, Box 357242, Seattle, WA 98195-7242. Phone: (206) 543-8837. Fax: (206) 685-0305. E-mail: honey{at}u.washington.edu.

Molecular and Cellular Biology, July 1999, p. 4757-4765, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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