Human breast cancer cells contain elevated levels and activity of the protein kinase, pkr

ABSTRACT PKR is a double-stranded (ds) RNA activated protein kinase whose expression is induced by interferon. Activated PKR phosphorylates its cellular substrate, eIF2, an essential

initiation factor of translation. Prior evidence from a murine model system suggested that PKR may act as a tumor suppressor, but the evidence from human tumors is equivocal. To study PKR

function in human breast cancer, PKR activity was measured in mammary carcinoma cell lines and nontransformed mammary epithelial cell lines. If PKR functioned as a tumor suppressor in this

system, its activity would be higher in nontransformed cells than in carcinoma cells. On the contrary, PKR autophosphorylation and the phosphorylation of its substrate, the α-subunit of

eIF2, is 7–40-fold higher in lysates prepared from breast carcinoma cell lines than in those from nontransformed epithelial cell lines. Correspondingly, a larger proportion of eIF2α is

present in a phosphorylated state in carcinoma cell lines than in nontransformed cell lines. Protein synthesis is not inhibited by the high eIF2α phosphorylation in carcinoma cells, probably

because they contain higher levels of eIF2B, the initiation factor that is inhibited by eIF2α phosphorylation. The dramatically lower PKR activity in nontransformed cell lines is partially

due to lower PKR protein levels (2–4-fold) as well as to the presence of a PKR inhibitor. The nontransformed cells contain P58, a known cellular inhibitor of PKR that physically interacts

with PKR and may be responsible for the low PKR activity in these cells. Taken together, these observations call into question the role of PKR as a tumor suppressor and suggest a positive

regulatory role of PKR in growth control of breast cancer cells. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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. 1998 _J. Biol. Chem._ 273: 25198–25202. * Zamanian-Daryoush M, Der SD and Williams BR. . 1999 _Oncogene_ 18: 315–326. Download references ACKNOWLEDGEMENTS This work was supported by seed

grant from the Dean's Biomedical Research Fund RA3467 and by NIH grant AI34552. We would like to thank R Wieder, M Clemens, JWB Hershey, M Katze and C Proud for cell lines and other

essential reagents. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, 185, South Orange Avenue, Newark, 07103,

New Jersey, NJ, USA Steve H Kim, Adam P Forman, Michael B Mathews & Shobha Gunnery * Department of Surgery, New Jersey Medical School, UMDNJ, 185, South Orange Avenue, Newark, 07103,

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also search for this author inPubMed Google Scholar * Michael B Mathews View author publications You can also search for this author inPubMed Google Scholar * Shobha Gunnery View author

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_et al._ Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR. _Oncogene_ 19, 3086–3094 (2000). https://doi.org/10.1038/sj.onc.1203632 Download citation

* Received: 13 December 1999 * Revised: 31 March 2000 * Accepted: 18 April 2000 * Published: 20 June 2000 * Issue Date: 22 June 2000 * DOI: https://doi.org/10.1038/sj.onc.1203632 SHARE THIS

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * PKR * breast cancer * translation * p58 * eIF2B